review article targeted delivery system of...

Review ArticleTargeted Delivery System of Nanobiomaterials inAnticancer Therapy From Cells to Clinics

Su-Eon Jin1 Hyo-Eon Jin2 and Soon-Sun Hong1

1 Department of Drug Development College of Medicine Inha University 3-ga Sinheung dong Jung-guIncheon 400-712 Republic of Korea

2Department of Bioengineering University of California Berkeley and Physical Biosciences DivisionLawrence Berkeley National Laboratory Berkeley CA 94720 USA

Correspondence should be addressed to Soon-Sun Hong hongsinhaackr

Received 25 November 2013 Accepted 25 December 2013 Published 19 February 2014

Academic Editor Dong-Wook Han

Copyright copy 2014 Su-Eon Jin et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancerNanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancerdrugs into the diseased sites In particular nanobiomaterial-based nanocarriers so-called nanoplatforms are the design of thetargeted delivery systems such as liposomes polymeric nanoparticlesmicelles nanoconjugates norganic materials carbon-basednanobiomaterials and bioinspired phage system which are based on the nanosize of 1ndash100 nm in diameter In this review the designand the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics We believe that this reviewcan offer recent advances in the targeted delivery systems of nanobiomaterials regarding in vitro and in vivo applications and thetranslation of nanobiomaterials to nanomedicine in anticancer therapy

1 Introduction

Cancer is a worldwide disease with a leading cause of mortal-ity accounting for about 580350 deaths almost 1600 peopleper day in 2013 from the statistical analysis of AmericanCancer Society in National Cancer Institute of the US [1]About 1660290 of new cancer cases are also expected to bediagnosed in 2013 The 5-year relative survival rate is stillsomewhat low at 68 for all cancers diagnosed between2002 and 2008 although it has been up from 49 in theperiod from 1975 to 1977 For this reason it is essential fortargeted therapy for cancer to reduce adverse reactions andmortality rate and to save costs in clinical practice Recentlytargeted anticancer therapeutics such asmonoclonal antibod-ies (mAbs) and tyrosine kinase inhibitors (TKIs) have beenapproved by the Food and Drug Administration (FDA) forthe treatment of cancer [2] The targeted therapy becomesan important element for the treatment of cancer as it helpsto develop the anticancer therapeutics based on imaging andtherapy (reducing the tumor size)

In this concept of targeted anticancer therapy nanoplat-forms are introduced with nanobiomaterial-based formula-tions or conjugation techniques in nanotechnology [3 4]Nanotechnology is a nanoscale-based technique in the fieldsof biomedical applications of pharmacology bioengineeringbiology and medicine [5] It currently relies on definitionsprovided by the National Nanotechnology Initiative (NNI)as follows [6] (1) development of research and technologyat the atomic molecular or macromolecular levels withinthe scale of nanosize of approximately 1 to 100 nanometerin range (2) devices and systems that have novel propertiesand functions based on the nanobiomaterials because of theirsmall andor intermediate size and (3) ability to control ormanipulate at the atomic level A variety of nanoparticularsystems span the range from a few nanometers to hundredsof nanometers When such nanoparticle-based systems areusually applied in solving the clinical problems we often usethe term ldquonanoplatformsrdquo [7]

Nanoplatforms have been developed to manufacturenanomedicines in preclinical and clinical studies for the

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 814208 23 pageshttpdxdoiorg1011552014814208

2 BioMed Research International

administration of small molecules genes and peptides withimprovement of given in vivo behavior [8ndash10] Figure 1shows the schematic diagrams of targeted delivery systemswith nanoplatforms such as liposome polymeric micellenanoconjugate gold nanoparticle carbon nanotube den-drimer and phage-based nanoplatform Several characteris-tics of an ideal tumor-targeted nanomedicine with nanoplat-forms are presented for translational research of ideal anti-cancer therapeutics as follows (1) increase of drug localiza-tion into the tumor by passive targeting or active targeting(2) decrease of drug localization in sensitive nontargetedand normal tissues (3) minimal drug leakage during transitto the target (4) prevention of degradation and prematureclearance of the drug (5) retainment of the drug at thetarget site during the desired period (6) facilitation of cellularuptake and intracellular trafficking and (7) biocompatibilityand biodegradability of nanoplatforms [10] Table 1 illustratesthe recently developed nanoplatforms for cancer targetingin preclinical studies We introduce recent studies of tar-geted anticancer system in the part of ldquorecently developednanoplatforms for cancer targeting in preclinical studiesrdquo

For successful translational research of nanoplatformsin anticancer therapy Doxil is an FDA approved drug forthe treatment of ovarian cancer which is a long-actingpegylated liposomal formulation of doxorubicin [11 12] Thisproduct is based on a study of liposomal drug deliverysystems for over four decades overcoming the limitationsof anticancer drug and liposomes such as poor stabilityand reproducibility [13 14] It is one of the successful casesfor the development of nanomedicines offering significantimprovements over doxorubicin alone in clinical useWe dealwith the translational research of nanomedicines in Table 2and introduce the anticancer drugs approved by FDA inTable 3 Based on the ideal characteristics of nanoplatformsthey can be designed for the following (1) sustained releaseof the drug (2) passive accumulation of the tumor tissue (3)ligand-based targeting of cell surface antigens or receptorswith the modulation of endosomal uptake and membranedisruption (4) drug release into the cytoplasm and (5)protection from enzymatic degradation [15 16] Additionallyin this review we demonstrate the applications of targeteddelivery systems from the cells to the clinics for anticancertherapy diagnostics nanoimaging bimodal imaging andreal-time intraoperative imaging

2 Mechanism of CancerTargeting by Nanoplatforms

Many nanobiomaterial-based platforms have been designedand evaluated for drug targeting to cancers as shown inFigure 2 Most of these platforms are ldquopassive targetingrdquoconcepts to improve the circulation time of the conjugated orencapsulated therapeutic drug such as liposomes polymersmicelles and nanoparticles Solid tumors have blood vesselswith enhanced vascular permeability and a lack of functionallymphatics which allow extravasation of carrier materialswith sizes of up to several hundreds of nanometers and

are unable to eliminate extravasated nanomaterials Fromthe several reports this EPR effect was shown even for theparticles size of 1-2120583m (eg Lactobacillus sp Salmonella spetc) which could make the particles accumulated in tumortissues [17 18] Therefore long-circulating nanomedicinesare able to be accumulated in tumors over time based ona mechanism known as the enhanced permeability andretention (EPR) effect [19 20] The EPR effect is a uniquephenomenon of solid tumors related to their anatomi-cal and pathophysiological differences from normal tissuesand is the most important strategy to improve the deliv-ery of therapeutic agents to tumors for anticancer drugdevelopment Examples of passively targeted nanoplatformsapproved for clinical use are Doxil (Caelyx in Europe pegy-lated liposomal doxorubicin) DaunoXome (nonpegylatedliposomal daunorubicin) DepoCyt (nonpegylated liposomalcytarabine) Myocet (nonpegylated liposomal doxorubicin)Oncaspar (pegylated L-asparaginase) Abraxane (albumin-based paclitaxel) and Genexol-PM (paclitaxel-containingpolymeric micelles approved in Korea) In particular Doxilis a pegylated liposome-based doxorubicin-loaded anti-cancer drug which is FDA approved for the treatmentof ovarian cancer as mentioned above This drug has asevere cardiotoxicity although it overcomes poor stabilityand reproducibility of liposomes and improves a biodis-tribution of doxorubicin in tumor tissues by EPR effectIn addition Abraxane is a Cremophor EL-free albumin-bound paclitaxel It reduced Cremophor EL-associated sideeffects of Taxol such as severe anaphylactoid hypersensitivityreactions hyperlipidaemia abnormal lipoprotein patternsaggregation of erythrocytes and peripheral neuropathy [21]Next-generation nanomedicines for anticancer therapy aredeveloping alternative approaches with recently developednanoplatforms minimizing side effects of surfactants informulations and targeting tumor tissues Several additionalpassively tumor-targeted nanomedicines are currently inclinical trials (Table 2) and many other ones are in early andlate-stage preclinical development [9 22ndash25]

On the other hand ldquoactive targetingrdquo strategy indicatesthe use of targeting ligands like antibodies and peptideswhich are attached to drugs and drug delivery nanoplatformsfor binding to receptor expressed at the target site In thisstrategy active targeting systems with ligands and antibodiesneed to be accumulated first in tumor tissues by EPReffect and then active targeting could be achieved Targetingligands for actively targeting nanomedicines are improvingcellular internalization via endocytosis-prone surface recep-tors such as folate [26] galactosamine [27] EGF [28] andtransferrin [29] To date targeting techniques for activetargeting are advanced at the preclinical level however onlyantibody-based nanomedicines have been approved for clin-ical use (Tables 2 and 3) Zevalin (CD20-targeted 90Yttrium-ibritumomab tiuxetan) Bexxar (CD20-targeted iodine-131tositumomab) Ontak (CD25-targeted diphtheria toxin-IL-2 fusion protein) and Mylotarg (CD33-targetd gemtuzumaboxogamicin) have been successfully used for non-Hodgkinrsquoslymphoma T-cell lymphoma and acutemyeloid leukemia Inaddition it has necessitated the use of peptides to enable the

BioMed Research International 3

(a) (b) (c) (d)

(e) (f) (g)

Targeting ligand

Au

Figure 1 Schematic diagrams of the targeted delivery systems (a) liposome (b) polymeric micelle (c) nanoconjugate (d) gold nanoparticle(e) carbon nanotube (f) dendrimer and (g) filamentous phage (M13 Fd)

cell internalization of cancer drugs such as cell-penetratingpeptides protein-transduction domains oligoarginine andTAT [30]

Active targeting to receptors which are overexpressedby angiogenic endothelial cells can reduce blood supply totumors that deprive the tumor cells from oxygen and nutri-ents in solid tumors Ligands used for drugs and drug deliveryplatforms to tumor vasculature include antibody fragmentL19 [31] as well as several cyclic and linear derivatives ofthe oligopeptide RGD and NGR which bind to angiogenicendothelium through the integrins (120572

2b1205733 120572v1205733 and 12057251205731)and aminopeptidase-N (CD13) respectively [32 33]

Although active targeting systems are extensively studiedto develop anticancer therapeutics there has been a lessexample of clinical use compared to passive targeting systemsDiscussing these problems to overcome active targetednanoplatforms are physicochemically unstable for bloodcirculation in the body and hard to be accumulated in tumortissues due to their size of conjugated targeting ligands offormulations (eg monoclonal antibodies) [34] In additionactive targeting systems can be eliminated by nanoparticularsurface opsonization (nonspecific protein adsorption) andnanoparticular uptake and retention to reticuloendothelialsystems resulting in poor efficiency of active targeting sys-tem in vivo [35] Based on these fundamental problemsand technical barriers multifunctionality targetability andstability are necessary to overcome the low efficiency of activetargeting nanoplatforms

3 Nanoplatforms of Anticancer Therapeuticsand Application in Clinical Trials

Targeted delivery systems of nanobiomaterials are currentlyin the process of developing nanoscale-sized platforms or

surface modification of nanoplatforms with active targetingligands that support multifunctionality due to poor solubilityof anticancer drugs or toxic effect of drugs on noncancerouscells and tissues [36 37] Most of the anticancer drugs arepoorly soluble or insoluble in water Thus organic solventsor toxic surfactants are usually applied for the formulationof anticancer therapeutics even used in clinics In additionanticancer drug alone has a toxic effect on normal cells andtissues without target specificity [38 39] Therefore severalnanoplatforms in 100 nm diameter based on nanobiomate-rials have been used to administer the anticancer drugs tominimize the adverse toxicity and tomaximize the drug effectwithin the therapeutic index [40]

Nanoplatforms offer solubility of poorly soluble anti-cancer drugs in water preparing soluble suspensions withthe minimum need for organic solvents and surfactantswhich cause toxicity [40 41] These platforms are accumu-lated in the tumor tissues by the EPR effect as mentionedabove The nanoplatforms are also used in the targeteddelivery systems of active targeting using the decorationwith receptor-targeted ligands or tumor antigen sensitiveantibodies together with anticancer drugs [22 37 42ndash44]The anticancer drugs encapsulated into the nanoplatformsspecifically liposomal nanoplatforms and polymer-basednanoplatforms are undergoing clinical trials [43 45 46]Table 2 shows the nanomedicines of anticancer drugs inclinical trials

31 Doxorubicin Doxorubicin a very effective anticancerdrug is widely used in the treatment of breast ovarianbladder and lung cancers [47] Mechanism of action ofdoxorubicin is the blocker of topoisomerase II which isan important enzyme in the DNA replication process thatunwinds the DNA helix The mechanisms of doxorubicin


Table1Re

centlydevelopednano

platform

sfor

cancer

targetingin

preclin

icalstu

dies

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Lipo

somes

Doxorub

icin

108

CyclicA

sn-G

ly-Arg

(cNGR)

peptidesCD13

and

aminop

eptid

aseN

cNGRdecorated

lysolip

id-con

tainingtemperature

sensitive

liposom

es

Hum

anfib

rosarcom

a(H

T-1080)

invitro

bind

ingstu

dy[95]

Lipo

somes

inorganic

nano

particles

(goldnano

rods

irono

xide

nano

worms)

Doxorub

icin

55

Atrun

cated

tumor-ta

rgeted

human

proteintissuefactor(tTF

RGD)toindu

cecoagulationon

bind

ingto

angiogenic120572]1205733receptors

toheatspecifically

directed

coagulation-cascade

activ

ationin

tumou

rs

ldquoSignallingrdquom

odules

(PEG

-decorated

gold

nano

rods

tumor-ta

rgeted

trun

catedtissue

factor

proteins)thattarget

tumorsa

ndthen

locally

activ

ate

thec

oagu

latio

ncascadeto

broadcasttum

orlocatio

nto

clot-targetedldquoreceivingrdquo

nano

particlesincirculationthat

carryad

iagn

ostic

ortherapeutic

cargo(iron

oxiden

anow

orms

doxorubicin-loaded

liposom

es)

Invivo

MDA-

MB-435

xeno

graft

tumors

ivinjectio

n[97]

Lipo

somes

carbon

nano

tubes

Paclitaxel

164

anti-ErBb

2(H

er2)

mAb

Each

nano

horn

encapsulated

with

inon

eimmun

oliposom

eform

ulated

with

PEGand

thermallysta

blea

ndpH

sensitive

phosph

olipidsfor

pHsensitive

andprolon

gedreleaseo

fpaclitaxel

SK-BR-3andBT

-20

breastcancer

cells

invitro

cytotoxicity

[98]

Polymericnano

particles

siRNA

80times320

mdash

Catio

niclipid-coatedPL

GA

nano

particlesau

niqu

esoft

litho

graphy

particlemolding

process(particlereplicationin

nonw

ettin

gtemplatesP

RINT)

Invitro

prostate

cancer

celllin

es[108]

Polymericmicelles

12-D

iaminocyclohexane-

platinum

(II)(D

ACHPt)(thep

arent

complex

ofoxaliplatin

)30

mdash

Long

-circ

ulatingdrug-lo

aded

polymericmicellese

nhancing

tumou

rpermeabilitywith

aTG

F120573inhibitor

Poorlyperm

eable

pancreatictumorsin

them

icem

odel(C

26or

BxPC

3tumors)

ivinjectio

n

[209]

Nanocon

jugates

Splice-sw

itching

oligon

ucleotides

(SSO

s)(pho

spho

rodiam

idate

morph

olinooligom

er(PMO))

13

RGDin

tegrin120572]1205733a

cell

surfa

ceglycop

rotein

thatis

preferentia

llyexpressed

inangiogenicendo

thelia

Album

in-based

nano

conjugates

with

fluorescencelabeling

which

ares

mallhigh

lyspecificand

noncytotoxic

Tumor

spheroidso

fA375GFP

cell

tumor

spheroid

study

usingA375GFP

cells

toconfi

rmtheu

ptake

andpenetrationof

nano

conjugates

inthree-dimensio

nal

(3D)c

ulture

[128]

BioMed Research International 5Ta

ble1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Paclitaxel

2-3

ultrasmallhyaluronica

cid

(HA)CD

44

Paclitaxel-u

ltrasmallH

A(3ndash5

kDa)

nano

conjugates

internalized

viaC

D44

receptor-m

ediatedendo

cytosis

which

allowed

paclitaxelto

bypasstheP

-glycoprotein-

mediatedeffl

uxon

thes

urface

ofcancer

cells

Brainmetastasis

ofbreastcancer

using

MDA-

MB-231Br

breastcancer

cells

ivinjectio

n

[129]

Goldnano

particles

Chem

iresistorsbasedon

functio

nalized

gold

nano

particlesin

combinatio

nwith

patte

rnrecogn

ition

metho

ds

5mdash

Asensor

arrayforb

reathtesting

ofexhaledbreath

inlung

cancer

patie

nts

Ano

ninvasive

diagno

stictoolfor

lung

cancer

invitro

array

[137]

Goldnano

particles

magnetic

microparticles

AnassayforP

SAdetectionwith

gold

nano

particlesb

ased

onthe

PSA-

specificA

bsandshortD

NA

sequ

ences(barcod

es)

30Prostate-specific

antig

en(PSA

)

Magnetic

microparticles

conjug

ated

with

PSA-

specific

antib

odiestoextracttrace

amou

ntso

fthe

targetanalyte

(PSA

)inserum

samples

from

patie

ntsa

ndgold

nano

particles

with

PSA-

specifica

ntibod

iesa

ndshortD

NAsequ

ences(the

barcod

es)atta

ched

todetectthis

analyte

Anultrasensitive

assayforp

rosta

tecancer

invitro

barcod

earray

[138]

Carbon

nano

tube

Sing

le-w

alledcarbon

nano

tube

(SWCN

T)with

fluorescence

labelling

200ndash

300

mdashBiod

istrib

utionandexam

ination

ofglom

erular

filtrationin

kidn

ey

NIR

fluorescence

imagingdynamic

PETim

aging

invitro

(HK-

2cells

atthetranswell)

invivo

(mice

NCr

nunu

)ivinjectio

n

[147]

Water

solublec

arbo

nnano

tubes

functio

nalized

with

PEGradio

labels

andRG

Dpeptide

1ndash5(diameter)

100ndash

300(le

ngth)

RGDin

tegrins120572

]1205733

RGD-pegylated

SWCN

Ts

radio-labelledSW

CNTs

U87MGhu

man

glioblastomaa

ndHT-29

human

colorectalcancer

cell

linesU

87MGand

HT-29

tumou

rxeno

graft

mod

elsfor

biod

istrib

ution(PET

)ivinjectio

n

[148]

Graph

ene

Nanograph

enes

heet(N

GS)

for

phototherm

altherapy(PTT

)10ndash50

mdashSix-armed

PEG-N

GSwith

fluorescent

labelin

g

4T1b

earin

gBa

lbc

miceKB

andU87MG

xeno

graft

mod

els

PTT

ivinjectio

n

[155]


Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage

ImagingandtherapyHSV

tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL

GApoly(lactic-co-glycolic)a

cidRG

Darginineglycineandasparticacid

(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom

alcamptothecinandextend

edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)

TF(ab1015840) 2fragmento

fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles

increasedpaclitaxelM

TD

high

respon

se

Metastatic

breastcancer

andurothelialcarcino

ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20

Polymericmicelle-based

activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser

ateIRRsinfusion-related

reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T

targeted(activetargetin

g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als

Cholesterylsulfate-based

amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio

npathologicmyopiaand

ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als

L-GlutamicacidL-alanine

L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D

L-lactide)paclitaxel

Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS

Fgranulocytecolony-stim

ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram

uscularirintravitreousitintrathecaliv

intravenou

sPE

Gpolyethyleneglycolsc

subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting

Active targeting Passive targeting

Specific receptor-ligand

interaction

Particular interaction with cell membraneSpecific endosomal

trafficking

Translational medicine

- Therapeutics- Diagnostics- Imaging

- Charged surface ofnanoplatforms

- Liposomal membrane- Small molecule ligand

- Targeting moiety ofnanoplatforms

- Peptide- Aptamer- Antibody

Figure 2 Overview of cancer targeting strategies from the cells to the clinics This overview illustrates the most clinically relevanttargeting strategies for anticancer therapy passive targeting and active targeting Passive targeting strategy is defined as the accumulationof nanoplatforms at the cancer cells by EPR effect which uses nanoplatforms without targeting moieties In this way particular interactionwill be proceeded to be internalized onto the cancer cells On the other hand active targeting strategy means the ligand-targeted or thereceptor-mediated approach based on the cancer-specific targeting moieties of nanoplatforms which interact with the specific receptor-ligand interaction on the cancer cells Based on the cancer targeting strategies translational medicine will be developed for the diagnosticstherapeutics and imaging

also include DNA cross-link and ROS generation besidesinhibiting topoisomerase II Based on these mechanisms ofaction doxorubicin has a potent antitumor activity in tumorcells inducing cell death However doxorubicin is associatedwith the severe side effects on the heart including irreversiblemyocardiotoxicity and fatal congestive heart failure [48] Todecrease the toxicity of doxorubicin nanoplatforms wereintroduced to enhance pharmacokinetic parameters with anaccumulation of drugs in the tumor tissues therebyminimiz-ing the cardiotoxicity Liposomes and polymeric nanoplat-forms were studied and developed as nanomedicines via anintravenous route Myocet MCC-465 MM-302 SP1049Cand NK911 are the liposomal or polymeric nanopaltformsof doxorubicin in the clinical trials [49] Myocet MCC-465and MM-302 are based on the liposomal nanoplatforms atthe range of 100ndash140 nm in diameter [50] In the cases ofMCC-465 andMM-302 the target-specific ligands of F (ab1015840)

2

fragment in human mAb GAH or tumor-specific antigenand scFvErbB2 (HER2) are incorporated into the liposomalnanoplatforms respectively In other words SP1049C andNK911 are used in the polymeric micelles SP1049C is aPluronic-based micellar formulation of doxorubicin [51] and

NK911 is a core-shell-type polymeric micellar nanoplatformof doxorubicin which consists of a block copolymer of PEG(mw 5000) and poly(aspartic acid) (30 units) conjugatedwith doxorubicin [52] Doxorubicin is entrapped into thehighly hydrophobic inner core of the polymeric micellarnanoplatforms

32 Paclitaxel Paclitaxel is a chemotherapeutic agent for theovarian breast and lung cancers as well as Kaposirsquos sarcoma[53] It is a mitotic inhibitor with a stabilizing activity ofthe microtubule assembly interfering the normal breakdownof microtubules during cell division Paclitaxel was origi-nally extracted from the Pacific yew tree Taxus brevifoliaBristol-Myers Squibb commercially developed paclitaxel afamous trademark TaxolHowever paclitaxel itself has severeadverse responses such as peripheral sensory neuropathy[54 55] anaphylaxis and hypersensitivity reactions due toits solubilizing materials (Cremophor EL and ethanol) [55]Therefore the development of nanoplatforms is essential toovercome these problems of formulation for the improve-ment of pharmacokinetic parameters and the toxic adverse


reactions in the normal tissues [56] EndoTAG-1 [57] LEP-ETU [58] Genexol-PM [59] NK105 [60] andOpaxio [61] aredeveloped as paclitaxel-loaded nanoplatforms undergoingclinical trials EndoTAG-1 and LEP-ETU are based on theliposomal nanoplatforms In particular EndoTAG-1 is basedon the cationic liposomal formulation which can interactwith the newly developed and negatively charged endothelialcells in the disease states for the growth of tumor bloodvessels targeting the blood supply to the tumor cells [57]Polymeric nanoplatform-based paclitaxel formulations arealso developed such as Genexol-PM NK105 and OpaxioPaclitaxel is conjugated to poly(l-glutamic acid) (PGA)in Opaxio [61] monomethoxy poly(ethylene glycol)-block-poly(DL-lactide) (mPEG-PDLL) in Genexol-PM [59] andNK105 polymers of PEG as the hydrophilic segment andmodified polyaspartate as the hydrophobic segment inNK105[62] respectively

33 Platinum-Based Anticancer Drugs Cisplatin (cisplat-inum or cis-diamminedichloroplatinum (II)) is also used inchemotherapy which is a platinum-based anticancer drug forthe treatment of various cancers including sarcomas somecarcinomas (eg small cell lung cancer and ovarian cancer)lymphomas and germ cell tumors [63 64] Mechanism ofaction in platinum-based anticancer drug is DNA cross-linking to interfere with the cell division by mitosis trig-gering apoptosis or cell death Oxaliplatin and carboplatinare also included in platinum-based anticancer therapeuticsIn clinical trials oxaliplatin (MBP-426) [65] and cisplatin(NC-6004 Nanoplatin) [66] are studied for their applica-bility to advancedmetastatic solid tumors In particularNanoplatin in combination with gemcitabine is evaluatedfor the treatment of advancedmetastatic pancreatic can-cers MBP-426 is reported as an oxaliplatin-based liposomalnanoformulation with the surface modification of transferrintargeting transferrin receptors in disease states In the case ofpolymeric nanoplatforms Nanoplatin a polymeric micelle-based cisplatin of 30 nm in diameter is studied for its kidneytoxicity reduction capabilities compared to cisplatin alone

34 Camptothecins Camptothecin and irinotecan a water-soluble derivative of camptothecin are cytotoxic alkaloidsisolated from Camptotheca acuminate [67] The target ofthese camptothecins and their derivatives is topoisomeraseI to inhibit the replication in the cells They bind to thetopoisomerase I and DNA complex generating a stabi-lized ternary complex to prevent DNA religation and tocause DNA damage resulting in apoptosis Camptothecinand its derivative are limitedly used due to lipophilicityand instability of the lactone ring structure by hydrolysisdespite their superior anticancer activity [68] Thereforethe nanoplatform-based camptothecin (S-CKD-602 [69] andCRLX101 [70]) and irinotecan (SN-38 NK012 [71]) are devel-oped undergoing clinical trials S-CKD-602 and CRLX101 areused in the nanoplatforms of a pegylated liposome and apolymeric micelle respectively In the case of irinotecan (SN-38 NK012) it is a polymeric micelle-based active metaboliteof camptothecin to exploit the EPR effect in the diameter

size of 20 nm This system is constructed in an amphiphilicblock copolymer PEG-PGlu (SN-38) by the self-assemblyin the aqueous media NK012 had an antitumor activitywith tolerance that included partial responses and severaloccurrences of prolonged stable disease across a variety ofadvanced refractory cancers in the clinical studies

35 GeneTherapy Plasmid DNA and siRNA for cancer genetherapy are also used for the treatment of cancers in theclinical trials The aim of gene therapy is to kill the cancercells blocking the transduction of the tumor cells or inhibitingthe disease-induced proteins without any damage to thenormal cells using cancer-specific genetic materials [72] Forthe current clinical trials p53 gene (SGT53-01) [73] RB94plasmid DNA (SGT-94) [74] and RRM2 siRNA (CALAA-01) [75] are studied for the treatment of solid tumors Thesematerials are based on tumor-specific nanoplatforms whichare the liposomal (SGT53-01 and SGT-94) or cyclodextrin-based nanoparticular (CALAA-01) systems decorated with atarget ligand of transferrin receptors in the tumor cellsThesenanoplatforms are necessary in delivering the genetic materi-als into the tumor cells due to the instability in the biologicalfluids (eg enzymatic digestion) and the hydrophilicity ofgenetic materials (eg poor uptake to cells)

4 Recently Developed Nanoplatforms forCancer Targeting in Preclinical Studies

41 Liposomes Liposomes have been developed as bioin-spired nanoplatforms which define the phospholipid bilayershowing the properties of the cell membrane [76 77] Theliposomal nanoplatform can carry the hydrophilic drug atthe aqueous core inside the bilayer and the hydrophobicdrug at the lipid membrane This nanoplatform has a lotof advantages for the delivery system with a great attentiongiven their biocompatibility and targetability from the in vitrocharacterization to translational research [50 78 79] Forcancer targeting liposomes are extensively used as passivetargeting agents and ligand-mediated or stimuli-sensitivetargeting agents (active targeting agents) [80] Based ontheir biocompatibility liposomes have been early devel-oped as nanoplatforms to transfer small molecules in thetumor tissues [14] Various anticancer drugs such as dox-orubicin doxorubicin derivatives paclitaxel and platinum-based anticancer drugs are usually loaded into the liposomalplatforms (Table 1) These are 100ndash200 nm in average sizewhich makes liposomes take a trip into the tumor tissues

Liposomes can also be used in the targeted delivery sys-temwith several modification of the liposomal surface design[81ndash84] Cancer targeting systems are rapidly used in broadapplications for the tumor-specific ligands [85 86] or tumor-associated antigens [87] although liposomes are possible to beused in anticancer therapy as the delivery carriers for passivecancer targeting The cancer-targeted therapy with targetingligands includes leukocyte differentiation antigen (CD33)for acute myeloid leukemia [88] GD2 for neuroblastoma[89] and the folate receptor for wide human tumors [9091] In addition integrins [92] vascular endothelial growth


factor receptors (VEGFR) [93] and CD13aminopeptidaseN [94] are also used as the targeting ligands Liposomeswith cyclic Asn-Gly-Arg (cNGR) peptide targeted to CD13were currently formulated with lysogenic lipids-loaded dox-orubicin for the potential treatment of human fibrosarcoma[95] These systems are not only ligand-targeted systemsfor cancer metastasis but also the hyperthermia-targetedsystems for tumor hyperthermia which regulates the releaseof doxorubicin specifically in the hyperthermal tissues forcancer targeting

Liposomes can also be used as one of the components inthe nanohybrid systems [96] A study by Von Maltzahn et alreported a complexed nanohybrid system for the treatmentof human breast cancer in the xenograft tumor model ofMDA-MB-435 cells [97] This system is the complex ofldquosignaling modulesrdquo to activate and broadcast the tumorlocation and ldquoreceiving modulesrdquo to carry the nanoplatform-based diagnostic agents and therapeutic drugs They usedthe doxorubicin-loaded liposomes as therapeutic cargos withiron oxide nanoworms as the diagnostic agents in circula-tion In addition for the activation of doxorubicin-loadedliposomal cargos PEG-decorated gold nanorods and tumor-targeted truncated tissue factor proteins (tTF-RGD) werepreviously introduced as the signaling modules to induce theheat specifically directed coagulation on binding to the angio-genic receptors in tumors before adding the doxorubicin-loaded liposomesThis system can be applied for the targetedtheranostic agents to detect and treat the tumors togetherLiposomes can also be used together with carbon nanotubes[98 99] Huang et al reported carbon nanotubes encapsu-lated into the liposomes which carried paclitaxel and anti-ErBb2 (Her2) mAb for this system SK-BR-3 and BT-20 breastcancer cells and checked the in vitro cytotoxicity [98] Thissystem can also be applied to theranostics for the potentialityof diagnostics and therapeutics

42 Polymeric NanoparticlesMicelles Polymers are inno-vative nanobiomaterials to be engineered for the deliverysystem of drugs genes and peptides [41 100] Polymericnanoparticles or micelles are easily prepared to be nanosizedwith various designs which are relatively smaller in sizecompared to lipid-based formulations that generally rangein size of 1ndash50 nm Polymers can be used to carry multipleligands for cancer targeting and imagingmolecules for cancerdiagnostics with a simple conjugation-based structural mod-ification [101] Among the polymers PEG and poly(lactic-co-glycolic) acid (PLGA) are extensively used as biocompatiblepolymers for translational medicine [102 103]

PLGA is one of the most widely used polymers due to itsbiocompatibility which is degraded to themonomers of lacticacid and glycolic acid in the body [104] PLGA was approvedby US FDA and European Medicine Agency (EMA) PLGA-based nanoparticles are successfully applied for drug deliveryof the biomedical approaches for the development of transla-tional medicine [105] For example paclitaxel-encapsulatedPLGA nanoparticles were formulated with a strong enhance-ment of the cytotoxic effect of paclitaxel on the tumor cellsin vitro and in vivo compared to commercial formulation

Taxol [106 107] Hasan et al published the cationic lipid-coated PLGA nanoparticles with a unique soft lithographyparticle molding process which was applied for the deliveryof siRNA in the prostate cancer cells [108] In this studythey coated the PLGA nanoparticles with cationic lipid fora successful internalization to the cells based on a charge-charge interaction of the cell membrane and nanoparticlesbecause PLGA has a negative charge Based on the additionof targeting ligands like cLABL (ICAM-1 targeting) [109]folate (folate receptor) [110 111] prostate-specific receptorantigen (prostate-specific receptor targeting) [112 113] RGD(integrins 120572V1205733) [114 115] and AS1411 (nucleolin targeting)[116 117] PLGA nanoparticles have the potential to improvedrug efficacy via target specificity of nanoplatforms in vitroand in vivo

Although these nanoparticles have an effective functionin cancer therapy in preclinical trials these nanoparticlescan be removed in circulation based on the biologicalbarrier and reticuloendothelial system (RES) which per-forms an opsonization to macrophages that are internalizedby phagocytosis [118] PEG is the most commonly usedpolymeric moiety for the surface modification of nanoplat-forms [119] Nanoparticles can be usually decorated withtargeting ligands conjugated with PEG PEG originally hasa function to make nanoparticles sterically stable for theprolonged circulation in the blood after administration Thismethod is called ldquopegylationrdquo [120] It demonstrates thehydrophilic moiety of PEG on the particular surface in thenanoplatforms which provides the steric hindrance of aparticular system to be shielded against the RES system fora prolonged delivery of the drug Aravind et al studied thelong-circulating drug-loaded polymeric micelles enhancingtumor permeability with a TGF120573 inhibitor in the poorlypermeable pancreatic tumors in amurinemodel of theC26 orBxPC3 tumors [116] They loaded 12-diaminocyclohexane-platinum(II)(DACHPt) which is the parent complex of oxali-platin in the polymeric micelles of PEG-b-poly(glutamicacid) (PEG-b-P(Glu)) copolymer and P(Glu) homopolymerAfter the size-based screening of permeability into thetumors 30 nm sized micelles had a relatively enhancedtumor permeability when transforming growth factor 120573 wasadministrated together with the micelles

43 Nanoconjugates Nanoconjugates have extensively beenstudied as the smart nanoplatforms with active functionalgroups to prepare the covalent binding for the anticancertherapeutics [121] Polymeric nanoconjugates are gener-ally synthesized with a simple conjugation of the func-tional groups in the polymer such as ndashOH ndashCOOH andndashNH2 These steps are stepwise reactions which need to

avoid uncontrollable side chemical synthesis Nanoconju-gates include the nanoplatforms of polymeric nanoparti-clesmicelles and other nanoparticles based on the charac-teristics of conjugation technique to prepare the nanocon-jugate platforms using the functional groups of nanobio-materials Polymer-drug conjugates [122 123] or mAb con-jugates [42] were reported for targeted anticancer therapyXiong et al introduced the cisplatin-based poly(120574 l-glutamicacid)-citric acid-based nanoconjugates [123] and Segal


and Satchi-Fainaro illustrated the polymeric nanoconjugate-based therapeutics with favorable polymers such as N-(2-hydroxypropyl)methacrylamide (HPMA) polyglutamic acid(PGA) and 120573-poly(L-malic acid) (Polycefin) [122] In addi-tion Julien et al showed mAb-targeted nanobiomaterials foranticancer therapy [42] They described the mAb-drug con-jugates with an introduction of mAb-based therapeutics suchas CD20 (Rituxan for B-cell lymphoma) HER2 (Herceptinfor breast cancer) VEGF (Avastin for colon lung breast andrenal cancer) and EGFR (Erbitux for colon and lung cancer)

These platforms have more advantages than othernanoplatforms like micelles and liposomes in the way thatthey are small in size and chemically stable in biologicalfluid For this reason these platforms are easily appliedto the functionalization of multiple-target ligands or ther-anostic agents with polymers peptides proteins or othernanoparticles For example folate is a widely used ligandfor cancer targeting which can have an interaction with theoverexpressed folate receptors in cancer states [124] Folatereceptors are highly overexpressed in epithelial ovariancervical breast lung kidney colorectal and brain tumorswhile they are restrictedly expressed in the normal tissuessuch as the lung kidney placenta and choroid plexus whichare limited to the apical surface of the polarized epithelia[124 125] Folate has a lot of advantages to be used for atargeting ligand through the conjugation to nanobiomaterialsbased on its small molecular weight (441Da) and the easypreparation method of folate-linked nanobiomaterials due tothe stability of folate over a broad range of temperatures andpH values [126] Zwicke et al focused on the folate-basednanoconjugates for anticancer therapy with doxorubicin orpaclitaxel and cancer imaging with other contrast agentslike gold nanoparticles iron oxide nanoparticles or carbonnanotubes [127]

The nanoconjugate systems can be the effective targetingnanoplatforms of macromolecules to the tumor tissues basedon their ultrasmall size although they carried the ligand-based targeting systems of cell surface antigens peptidesor polymers The albumin-based nanoconjugates were intro-duced by Ming et al [128] which carried phosphorodi-amidate morpholino oligomer (PMO) type splice-switchingoligonucleotides (SSOs) with a RGD peptide for integrin120572V1205733 a cell surface glycoprotein as an active targeting ligandand a fluorescence labelThis system was very small based on13 nm of size It had a high specificity without cytotoxicity Inparticular it was applied to the tumor spheroids of A375 cellsto check the uptake and penetration of the albumin-basednanoconjugates into the three-dimensional (3D) cultures Inaddition these nanoconjugates can overcome the drawbacksof conventional chemotherapy such as drug toxicity to nor-mal cells and cancer drug resistance by specific targetingand activating the cancer cells via the multiple decorationsof target ligands on the nanoconjugates Mittapalli et alalso reported the paclitaxel-ultrasmall hyaluronic acid (HA)nanoconjugates [129] which is a CD44 receptor targetingsystem for the treatment of brain metastasis of breast cancerin a model of MDA-MB-231 breast cancer cells They used anultrasmall HA (3ndash5 kDa) as a target ligand to interact withCD44 receptors on the surface of the cancer cells In addition

this ultrasmall HA-mediated cellular uptake of paclitaxelavoided the P-glycoprotein-mediated efflux showing the drugresistance in cancer cells In particular this system exhibiteda small size of 2-3 nm like a single molecule of the nanocon-jugates and can self-assemble into larger particles

44 Inorganic NanoparticlesmdashIron Oxide Nanoparticles Sup-erparamagnetic Iron Oxide Nanoparticles and Gold Nanopar-ticles Inorganic nanoparticles have been currently investi-gated as contrast agents in clinical practice [130] Iron oxidenanoparticles and superparamagnetic iron oxide nanoparti-cles have been studied extensively as contrast agents becausethey enhance the negative contrasts and give us darker imagesof the interest regions in magnetic resonance imaging (MRI)Iron oxide nanoparticles have a magnetic moment to bechanged by an ambient thermal energyThis system has beenwidely used forMRI contrast enhancements as well as tissue-specific release of therapeutic agents [131] Superparamag-netic iron oxide (SPIO) nanoparticles are either form whichincludes the inside of the core of magnetic nanoparticleswith a polymeric coating or a homogeneous integrationinto the polymeric nanoparticles [4] This nanoparticularsystem has a small size with the range of 3ndash6 nm of the coresize and 20ndash150 nm after dextran coating such as Feridexand Combidex which is a superior biocompatible magneticmaterial-based biomedical technique with respect to othermagnetic materials both based on oxides or pure metals[132] In addition this system can deliver anticancer drugssuch as doxorubicin and methotrexate which is used astheranostic cargo system due to its small size [133 134] Inaddition the gold nanoparticles were used together with theiron oxide nanoparticles to study the MRI contrast agents aswell as the optical probes exploiting the reflectance signal ofthe gold nanoparticles [135]

The gold nanoparticles can also be used in an ultrasen-sitive assay technique to detect cancers [136] Peng et alintroduced the functionalized gold nanoparticles in com-bination with the pattern recognition methods to diagnosethe lung cancer from breath testing [137] This methodis an in vitro sensor array technique of the detection ofbiomarkers in exhaled breath of lung cancer patients asa noninvasive diagnostic tool In addition Thaxton et alreported the combination system based on the magneticmicroparticles and the gold nanoparticles conjugated withthe prostate-specific antigen- (PSA-) specific antibodies todiagnose prostate cancers [138] In this system the magneticmicroparticles conjugated with PSA-specific antibodies wereused to extract the traceable amounts of PSA in the serumsamples from patients and the gold nanoparticles with PSA-specific antibodies and short DNA sequences (the barcodes)were attached to detect this analyte for in vitro barcode assay

45 Carbon-Based NanoplatformsmdashCarbon Nanotubes andGraphene Graphite is one of the carbon-based natural mate-rials that are widely used in large-scale industrial appli-cations such as steelmaking and battery electrodes [139]From graphite carbon-based nanobiomaterials have beenengineered with the deeper nanofabrication techniques


which include carbon nanotubes and graphene [140] Thesenanobiomaterials are currently and widely regarded ashighly attractive biomedical application systems that have amultifunctional nature In addition they are incorporatedinto the conventional existing nanobiomaterials so-called thehybrid system with further function [141 142]

Carbon nanotubes are cylindrical nanostructure-basedcarbon materials which are synthesized by an arc dischargeor chemical vapor deposition of graphite [143] They areshaped like rolling sheets of carbon into the hollow tubesTheir sizes are ultrasmall 04 to 2 nm in diameter of single-walled carbon nanotubes (SWCNTs) [144 145] This systemcan also be modified to be suitable for biological applicationswith an addition of functional groups targeting moleculesand polymers and so forth to enhance the solubility andbiocompatibility [146] Ruggiero et al studied the biodistri-bution and glomerular filtration in the kidney of SWCNTwith fluorescence label This system was applied to the nearinfrared (NIR) fluorescence imaging and dynamic positronemission tomography (PET) imaging [147] For the enhance-ment of solubility of the carbon nanotubes Liu et al reportedthe water soluble carbon nanotubes functionalized withPEG [148] In addition this water soluble carbon nanotubesystem with radio labels and RGD peptide targeted integrins120572V1205733 for the treatment of human glioblastoma and humancolorectal cancer in the U87MG and HT-29 tumor xenograftmodels They checked the biodistribution of this systemusing PET scan in the murine tumor model after intravenousinjection

Graphene is a single planar sheet structured carbon-based material which is a single atomic plane of graphitein a honey comb crystal lattice [149] It is isolated bya simple method for extracting graphene from graphitevia exfoliation [150] Graphene is similar to carbon nan-otubes in that it has similar electrical optical and ther-mal properties although the structure of graphene is two-dimensional atomic sheet different from carbon nanotubes[151] Graphene can be an attractive material since it hasthe possibility of being engineered to be structurally thinand flexible For the biomedical applications graphene oxideand reduced graphene oxide are more commonly used dueto its solubility in aqueous environments and capabilityof chemical functionalization [152] Graphene oxide wasproduced by the oxidation of graphite under acidic condi-tions (eg the modified Hummerrsquos method) and reducedgraphene oxide was provided from a reduction of grapheneoxide with several reducing reagents (eg hydrazine) [153]They are applied to the biomedical nanomedicine includinginjectable drug delivery systems for anticancer therapy ascarbon nanotubes [154] For example the nanographenesheet (NGS) for photothermal therapy (PTT) was reportedby Shi et al [155] which was a six-armed PEG-NGS of10ndash50 nm in size with fluorescence labeling for PTT ofcancers in the models of 4T1 bearing Balbc mice as wellas KB and U87MG xenograft models after intravenousinjection In addition reduced graphene oxide was appliedto PTT in tumor models by Yang et al [156] who usedthe reduced graphene oxide conjugated with the chimeric

form of anti-CD105 mAb TRC 105 to target and detectthe tumor vasculature in the living mice as a theranosticagent

46 Dendrimers Dendrimers are three-dimensional sph-erical-shaped nanobiomaterials with repeated branches ofdendron which contains a single chemical group called afocal point [157 158] The structure of dendrimers consistsof a core of initiator repeated branching units termi-nal functional groups and void spaces which are roomsfor molecular cargo [159] In the globular and nanosizedstructures of dendrimers the terminal functional groupsof the outer surface are essential in determining the prop-erties of dendritic macromolecules which can be inter-acted and conjugated with other molecules to target thecancer cells and tissues The commonly used dendrimersin nanomedicines are polyamidoamines (PAMAM) [160]poly(L-lysine) scaffold dendrimers (PLL) [161] polyesters(PGLSA-OH) [162] polypropylimines (PPI) [163] andpoly(22-bis(hydroxymethyl) propionic acid scaffold den-drimers (bis-MPA) [164] Some of them are commerciallyavailable such as PAMAM dendrimers (Starburst) and PPIdendrimers (Astramol) [165 166] Dendrimers can be appliedto cancer targeting conjugated with the targeting ligandssuch as folate transferrin antibodies peptides and aptamers[167] In addition multifunctionality of dendrimers can bea major advantage based on an incorporation of anticancertherapeutics as well as imaging agents [158 165 168]

47 Virus-Based Nanoplatforms (Phage System) Virus-basednanomaterials have been dramatically investigated in recentyears [169] Viruses are biochemical complexes composedof genomic and proteomic materials The desired functionsof materials for bionanomedicine can be engineered bydesigning the shape and size of nanoparticles as well as thespecific sequence of DNA and proteins The self-assembledviral architecture can occur in awide range of shapes and sizes[170] and can offer remarkable structural features of virusthat make them excellent candidates for bionanomedicine[171 172] Advancements in nanoscale biological engineeringof viral particles provide a development of novel pathways todevelop nanomedicine for cancer therapeutics Various typesof viruses such as adenovirus adeno-associated virus andbacteriophages have been utilized for targeted cancer therapyand imaging through genetic and chemical modifications ofthe virus [173ndash175]

A bacteriophage (phage) is a prokaryotic virus that caninfect the bacterial host cells exploiting the hostrsquos biosyntheticmachinery to produce many identical copies of the phageitself [176] There are many types of phages with differentgenomic materials replication processes and shapes suchas linear (M13 Fd and F1) [177] or spherical (MS2) [178]Some shapes are quite sophisticated for example T4 and T7phages possess an icosahedral head and a long tail connectedthrough a cylindrical body [170] Over the last two decadesthe biochemical landscape of the phage structure has beengreatly expanded through genetic engineering [179ndash182] andsite-specific organic synthesis approaches [183ndash186]Through


genetic engineering many foreign or synthetic DNAs havebeen integrated into the phage genome and expressed atvarious sites of the phage body [182 187] Several groups areinvestigating the engineered filamentous bacteriophage forin vivo screening via phage display within organs [188] orcancerous tissue [189 190] for the purpose of targeted drugdelivery [191 192] or as an imaging agent [193] For genedelivery applications therapeutic genetic material can beincorporated into the phage DNA and carried into the cellsfollowing a receptor uptake [194] The phage can be locallytargeted to the cell receptors by incorporation of specifictargeting andor internalization peptides (ie via RGD orother ligands) To make the phage even more effective thanthe DNA delivery vehicles phage can be further decoratedwith peptides that facilitate endosomal escape or nuclearlocalization motifs that target the nuclear envelope [195]The most widely used bacteriophages for gene delivery areM13 filamentous phages [173 196 197] and lambda phages[198] To enhance gene delivery efficiency the phage with themultifunctional peptides can be produced using a phagemidsystem which facilitates manipulation of expressed proteinson viral vectors [197] Phage display technology has allowedfor identification of novel homing peptides that targetthe unknown cell surface proteins The targeting peptidescan be incorporated into the phage coat proteins throughgenetic engineering techniques or chemical modificationsto improve targeting efficiency [194] These include peptides(RGD glioma-binding peptide) [197 199] HER2 receptortargeting antibody [173] growth factors (EGF and FGF2)[200 201] and the penton base of adenovirus [198] Hajitou etal constructed a hybrid phage with two genes from the phageand nucleus integrating gene from an adeno-associated virus(AAV) called inverted terminal repeats [194] Althougheukaryotic viruses such as AAV have fantastic transgenedelivery capabilities they require an elimination of thenative tropism for mammalian cells In contrast M13 phageshave no tropism for mammalian cells however their genedelivery efficiency is poor Thus there has been an effortto combine the advantageous aspects of AAV and M13phages into a single system [194] This phage displayedintegrin-binding peptides (cyclic RGD) on the minor coatproteins and carried the herpes simplex virus thymidinekinase gene (HSVtk) The resulting AAVphage systemprovided a superior tumor transduction over the phage aloneand was used as the PET imaging agent with [18F]FDG and[18F]FEAU as well as cancer therapeutics with ganciclovirtreatment (Table 1) Ghosh et al investigated the selectivetumor targeting phage-based material for in vivo imagingfor prostate cancer acidic and rich in cysteine (SPARC)which is upregulated in various cancers and correlatedwith poor prognosis [202] The capsid organization of M13spatially separates the targeting and imaging moietiesUsing p3 to display the targeting ligands (SPARC-bindingpeptide SPPTGIN) while assembling multiple magnetic ironoxide nanoparticles (MNPs) along the p8 capsid achieveseffective targeting and delivers a larger payload of MNPs perSPARC compared with directly functionalized nanoparticles(Table 1) Compared with nanoparticles that are directly

functionalized with targeting peptides this approachimproves the contrast because each SPARC-targetingmolecule delivers a larger number of nanoparticles intothe cells Moreover the targeting ligand and nanoparticlescould be easily exchanged for others making this platformattractive for in vivo screening and molecular detection(Table 1)

5 Applications of Targeted Delivery Systemsfrom Cells to Clinics

Nanoplatforms generally have the potential to be appliedas cancer diagnosis imaging and treatment in vitro andin vivo Targeted delivery strategies of nanoplatforms arespecial formulations and carriers with anticancer drugs suchas pegylated liposomes polymeric nanoparticlesmicellesand albumin-based drug carriers These nanoplatforms thatwe mentioned above can be applicable to the biomedicalapproaches such as cancer diagnostics [145] anticancertherapy [203] nanoimaging [204] bimodal imaging [205206] and real-time intraoperative imaging [26] The FDAhas approved clinical use of a significant number of anti-cancer drug products in the nanometer size range includingthe applications in Table 3 In particular nanoimaging hasbecome based on the diagnostic potential of an earlierdetection in the cancer and other human diseases [207]In the case of bimodal contrast imaging bimodal contrastagents allow the assessment of regions of interest using twoindependent imaging modalities such as MRI reagents andfluorescent agents In the case of MRI and fluorescence imag-ing MRI has an excellent spatial resolution and fluorescenceimaging compensates for the sensitivity of MRI overcomingthe limitations of a single-modality imaging [208] Forintraoperative fluorescence imaging the first human trialin advanced-stage ovarian cancer proceeded with tumor-specific folate receptor-120572 targeted fluorescent agent [26]Thisstudy offers the potential application of intraoperative stagingwith tumor-specific fluorescence imaging in patients withovarian cancer by folate receptor-120572 overexpression

6 Conclusion

Human genomic map has accelerated the current biomedicalapplication for the improvement of human healthcare andfuture therapies encompassing a full understanding of thegene function Increasing information regarding the generegulation process will provide the fundamental knowl-edge for the development of novel therapy in the diseasestate of cancer For this streamline of biomedical researchnanoplatforms can take the center stage of participating inthe development of targeted nanomedicine for anticancertherapy in the foreseeable future Using these nanoplatformtechniques targeted anticancer therapy of nanomedicinewithout toxicity will be able to detect confirm and treatvarious types of cancers as a part of personalized medicineThis therapeutic potential will require more approaches todevelop ideal targeted nanoplatforms overcoming toxicityand enhancing biocompatibility as well as multifunctionality


of nanoplatforms We believe that these cancer targetingstudies of nanoplatforms can contribute to the scientificachievement of nanotechnology and nanoplatforms for thedevelopment of targeted anticancer therapeutics

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work is supported by Korean Health Technology RampDProject (A120266) Ministry of Health and Welfare theNational Research Foundation of Korea (NRF) funded bythe Ministry of Education Science and Technology (NRF-2012-0002988 2012R1A2A2A01045602) and Inha Universitygrant

References

[1] American Cancer Society Cancer Facts and Figures 2013American Cancer Society Atlanta Ga USA 2013

[2] S Svenson ldquoClinical translation of nanomedicinesrdquo CurrentOpinion in Solid State and Materials Science vol 16 no 6 pp287ndash294 2012

[3] A M Mohs and J M Provenzale ldquoApplications of nanotech-nology to imaging and therapy of brain tumorsrdquo NeuroimagingClinics of North America vol 20 no 3 pp 283ndash292 2010

[4] Y-E L Koo G R Reddy M Bhojani et al ldquoBrain cancerdiagnosis and therapy with nanoplatformsrdquo Advanced DrugDelivery Reviews vol 58 no 14 pp 1556ndash1577 2006

[5] National Nanotechnology Initiative (NNI) ldquoWhat is nanotech-nologyrdquo httpwwwnanogov

[6] H S Choi and J V Frangioni ldquoNanoparticles for biomedicalimaging fundamentals of clinical translationrdquoMolecular Imag-ing vol 9 no 6 pp 291ndash310 2010

[7] J Shi A R Votruba O C Farokhzad and R Langer ldquoNan-otechnology in drug delivery and tissue engineering fromdiscovery to applicationsrdquoNano Letters vol 10 no 9 pp 3223ndash3230 2010

[8] L Zhang F X Gu J M Chan A Z Wang R S Langerand O C Farokhzad ldquoNanoparticles in medicine therapeuticapplications and developmentsrdquo Clinical Pharmacology andTherapeutics vol 83 no 5 pp 761ndash769 2007

[9] T Lammers W E Hennink and G Storm ldquoTumour-targetednanomedicines principles and practicerdquo British Journal ofCancer vol 99 no 3 pp 392ndash397 2008

[10] T Lammers F Kiessling W E Hennink and G StormldquoDrug targeting to tumors principles pitfalls and (pre-) clinicalprogressrdquo Journal of Controlled Release vol 161 no 2 pp 175ndash187 2012

[11] D W Northfelt B J Dezube J A Thommes et al ldquoPegylated-liposomal doxorubicin versus doxorubicin bleomycin andvincristine in the treatment of AIDS-related Kaposirsquos sarcomaresults of a randomized phase III clinical trialrdquo Journal ofClinical Oncology vol 16 no 7 pp 2445ndash2451 1998

[12] R Strother and D Matei ldquoPegylated liposomal doxorubicin inovarian cancerrdquo Therapeutics and Clinical Risk Managementvol 5 no 3 pp 639ndash650 2009

[13] A D Bangham M M Standish and J C Watkins ldquoDiffusionof univalent ions across the lamellae of swollen phospholipidsrdquoJournal of Molecular Biology vol 13 no 1 pp 238ndash252 1965

[14] K Sen and M Mandal ldquoSecond generation liposomal cancertherapeutics transition from laboratory to clinicrdquo InternationalJournal of Pharmaceutics vol 448 no 1 pp 28ndash43 2013

[15] H Maeda H Nakamura and J Fang ldquoThe EPR effect formacromolecular drug delivery to solid tumors improvement oftumor uptake lowering of systemic toxicity and distinct tumorimaging in vivordquo Advanced Drug Delivery Reviews vol 65 no1 pp 71ndash79 2013

[16] O C Farokhzad and R Langer ldquoImpact of nanotechnology ondrug deliveryrdquo ACS Nano vol 3 no 1 pp 16ndash20 2009

[17] M Zhao M Yang X-M Li et al ldquoTumor-targeting bacte-rial therapy with amino acid auxotrophs of GFP-expressingSalmonella typhimuriumrdquo Proceedings of the National Academyof Sciences of the United States of America vol 102 no 3 pp755ndash760 2005

[18] N T Kimura S Taniguchi K Aoki and T Baba ldquoSelectivelocalization and growth of Bifidobacterium bifidum in mousetumors following intravenous administrationrdquoCancer Researchvol 40 no 6 pp 2061ndash2068 1980

[19] Y Matsumura and H Maeda ldquoA new concept for macro-molecular therapeutics in cancer chemotherapy mechanism oftumoritropic accumulation of proteins and the antitumor agentsmancsrdquo Cancer Research vol 46 no 12 part 1 pp 6387ndash63921986

[20] J Fang H Nakamura and H Maeda ldquoThe EPR effect uniquefeatures of tumor blood vessels for drug delivery factorsinvolved and limitations and augmentation of the effectrdquoAdvancedDrugDelivery Reviews vol 63 no 3 pp 136ndash151 2011

[21] H Gelderblom J Verweij K Nooter and A SparreboomldquoCremophor EL the drawbacks and advantages of vehicleselection for drug formulationrdquoEuropean Journal of Cancer vol37 no 13 pp 1590ndash1598 2001

[22] TMAllen andP R Cullis ldquoDrug delivery systems entering themainstreamrdquo Science vol 303 no 5665 pp 1818ndash1822 2004

[23] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancertherapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007

[24] M E Davis Z Chen and D M Shin ldquoNanoparticle thera-peutics an emerging treatment modality for cancerrdquo NatureReviews Drug Discovery vol 7 no 9 pp 771ndash782 2008

[25] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010

[26] G M Van Dam G Themelis L M A Crane et al ldquoIntraop-erative tumor-specific fluorescence imaging in ovarian cancerby folate receptor-120572 targeting first in-human resultsrdquo NatureMedicine vol 17 no 10 pp 1315ndash1319 2011

[27] L W Seymour D R Ferry D Anderson et al ldquoHepatic drugtargeting phase I evaluation of polymer-bound doxorubicinrdquoJournal of Clinical Oncology vol 20 no 6 pp 1668ndash1676 2002

[28] G D Lewis Phillips G Li D L Dugger et al ldquoTargetingHER2-positive breast cancer with trastuzumab-DM1 an antibody-cytotoxic drug conjugaterdquo Cancer Research vol 68 no 22 pp9280ndash9290 2008

[29] Z M Qian H Li H Sun and K Ho ldquoTargeted drug deliveryvia the transferrin receptor-mediated endocytosis pathwayrdquoPharmacological Reviews vol 54 no 4 pp 561ndash587 2002


[30] B Gupta T S Levchenko and V P Torchilin ldquoIntracellu-lar delivery of large molecules and small particles by cell-penetrating proteins and peptidesrdquo Advanced Drug DeliveryReviews vol 57 no 4 pp 637ndash651 2005

[31] D Neri and R Bicknell ldquoTumour vascular targetingrdquo NatureReviews Cancer vol 5 no 6 pp 436ndash446 2005

[32] K Temming R M Schiffelers G Molema and R J KokldquoRGD-based strategies for selective delivery of therapeutics andimaging agents to the tumour vasculaturerdquo Drug ResistanceUpdates vol 8 no 6 pp 381ndash402 2005

[33] R Pasqualini E Koivunen R Kain et al ldquoAminopeptidase N isa receptor for tumor-homing peptides and a target for inhibitingangiogenesisrdquoCancer Research vol 60 no 3 pp 722ndash727 2000

[34] Y Matsumura and K Kataoka ldquoPreclinical and clinical studiesof anticancer agent-incorporating polymer micellesrdquo CancerScience vol 100 no 4 pp 572ndash579 2009

[35] S Nie ldquoEditorial understanding and overcoming major barri-ers in cancer nanomedicinerdquo Nanomedicine vol 5 no 4 pp523ndash528 2010

[36] F Perche and V P Torchilin ldquoRecent trends in multifunctionalliposomal nanocarriers for enhanced tumor targetingrdquo Journalof Drug Delivery vol 2013 Article ID 705265 32 pages 2013

[37] A Srivastavaa I B O rsquoConnora A Panditb and J G WallldquoPolymer-antibody fragment conjugates for biomedical appli-cationsrdquo Progress in Polymer Science 2013

[38] P E Kintzel and R T Dorr ldquoAnticancer drug renal toxicityand elimination dosing guidelines for altered renal functionrdquoCancer Treatment Reviews vol 21 no 1 pp 33ndash64 1995

[39] A Remesh ldquoToxicities of anticancer drugs and its manage-mentrdquo International Journal of Basic amp Clinical Pharmacologyvol 1 no 1 pp 2ndash12 2012


[41] N Kamaly Z Xiao P M Valencia A F Radovic-Moreno andO C Farokhzad ldquoTargeted polymeric therapeutic nanoparti-cles design development and clinical translationrdquo ChemicalSociety Reviews vol 41 no 7 pp 2971ndash3010 2012

[42] D C Julien S Behnke GWang G KMurdoch and R A HillldquoUtilization of monoclonal antibody-targeted nanomaterials inthe treatment of cancerrdquomAbs vol 3 no 5 pp 467ndash478 2011

[43] J Kopecek ldquoPolymer-drug conjugates origins progress to dateand future directionsrdquoAdvanced Drug Delivery Reviews vol 65no 1 pp 49ndash59 2013

[44] A Accardo D Tesauro and G Morelli ldquoPeptide-based tar-geting strategies for simultaneous imaging and therapy withnanovectorsrdquo Polymer Journal vol 45 no 5 pp 481ndash493 2013

[45] S Sofou ldquoSurface-active liposomes for targeted cancer therapyrdquoNanomedicine vol 2 no 5 pp 711ndash724 2007

[46] M Wang and M Thanou ldquoTargeting nanoparticles to cancerrdquoPharmacological Research vol 62 no 2 pp 90ndash99 2010

[47] O Tacar P Sriamornsak and C R Dass ldquoDoxorubicin anupdate on anticancer molecular action toxicity and novel drugdelivery systemsrdquo Journal of Pharmacy and Pharmacology vol65 no 2 pp 157ndash170 2013

[48] M Volkova and R Russell III ldquoAnthracycline cardiotoxicityprevalence pathogenesis and treatmentrdquo Current CardiologyReviews vol 7 no 4 pp 214ndash220 2011

[49] V Krishnan and A K Rajasekaran ldquoClinical nanomedicine asolution to the chemotherapy conundrum in pediatric leukemiatherapyrdquo Clinical Pharmacology andTherapeutics 2013

[50] R van derMeela L J C Vehmeijera R J Koka G Storma andE V B van Gaala ldquoLigand-targeted particulate nanomedicinesundergoing clinical evaluation current statusrdquo Advanced DrugDelivery Reviews vol 65 no 10 pp 1284ndash1298 2013

[51] D Y Alakhova Y Zhao S Li and A V Kabanov ldquoEffect of dox-orubicinpluronic SP1049C on tumorigenicity aggressivenessDNA methylation and stem cell markers in murine leukemiardquoPloS ONE vol 8 no 8 Article ID e72238 2013

[52] Y Matsumura T Hamaguchi T Ura et al ldquoPhase I clinicaltrial and pharmacokinetic evaluation of NK911 a micelle-encapsulated doxorubicinrdquo British Journal of Cancer vol 91 no10 pp 1775ndash1781 2004

[53] P Cozzi N Mongelli and A Suarato ldquoRecent anticancercytotoxic agentsrdquo Current Medicinal Chemistry-Anti-CancerAgents vol 4 no 2 pp 93ndash121 2004

[54] E K RowinskyMWright BMonsarrat and R C DonehowerldquoClinical pharmacology and metabolism of Taxol (paclitaxel)update 1993rdquoAnnals of Oncology vol 5 supplement pp S7ndashS161994

[55] E K Rowinsky and R C Donehower ldquoDrug therapy paclitaxel(taxol)rdquo The New England Journal of Medicine vol 332 no 15pp 1004ndash1014 1995

[56] H A Azim Jr and A Awada ldquoClinical development of newformulations of cytotoxics in solid tumorsrdquo Current Opinion inOncology vol 24 no 3 pp 325ndash331 2012

[57] U Fasol A Frost M Buchert et al ldquoVascular and pharmacoki-netic effects of EndoTAG-1 in patients with advanced cancerand livermetastasisrdquoAnnals ofOncology vol 23 no 4 pp 1030ndash1036 2012

[58] S Koudelka and J Turanek ldquoLiposomal paclitaxel formula-tionsrdquo Journal of Controlled Release vol 163 no 3 pp 322ndash3342012

[59] T-Y Kim D-W Kim J-Y Chung et al ldquoPhase I and pharma-cokinetic study of Genexol-PM a Cremophor-free polymericmicelle-formulated paclitaxel in patients with advanced malig-nanciesrdquo Clinical Cancer Research vol 10 no 11 pp 3708ndash37162004

[60] T Negishi F Koizumi H Uchino et al ldquoNK105 a paclitaxel-incorporating micellar nanoparticle is a more potent radiosen-sitising agent compared to free paclitaxelrdquo British Journal ofCancer vol 95 no 5 pp 601ndash606 2006

[61] V L Galic T J Herzog J D Wright and S N LewinldquoPaclitaxel poliglumex for ovarian cancerrdquo Expert Opinion onInvestigational Drugs vol 20 no 6 pp 813ndash821 2011

[62] T Hamaguchi Y Matsumura M Suzuki et al ldquoNK105 apaclitaxel-incorporatingmicellar nanoparticle formulation canextend in vivo antitumour activity and reduce the neurotoxicityof paclitaxelrdquo British Journal of Cancer vol 92 no 7 pp 1240ndash1246 2005

[63] XWang and Z Guo ldquoTargeting and delivery of platinum-basedanticancer drugsrdquo Chemical Society Reviews vol 42 no 1 pp202ndash2224 2013

[64] J S Butler and P J Sadler ldquoTargeted delivery of platinum-basedanticancer complexesrdquo Current Opinion in Chemical Biologyvol 17 no 2 pp 175ndash188 2013

[65] W C Zamboni ldquoConcept and clinical evaluation of carrier-mediated anticancer agentsrdquo Oncologist vol 13 no 3 pp 248ndash260 2008

[66] R Plummer R H Wilson H Calvert et al ldquoA Phase I clinicalstudy of cisplatin-incorporated polymeric micelles (NC-6004)in patients with solid tumoursrdquo British Journal of Cancer vol104 no 4 pp 593ndash598 2011


[67] I Kumler N Brunner J Stenvang E Balslev and D L NielsenldquoA systematic review on topoisomerase 1 inhibition in thetreatment of metastatic breast cancerrdquo Breast Cancer Researchand Treatment vol 138 no 2 pp 347ndash358 2013

[68] L Zhang Y Hu X Jiang C Yang W Lu and Y H YangldquoCamptothecin derivative-loaded poly(caprolactone-co-lacti-de)-b-PEG-b- poly(caprolactone-co-lactide) nanoparticles andtheir biodistribution in micerdquo Journal of Controlled Release vol96 no 1 pp 135ndash148 2004

[69] W C Zamboni S Ramalingam D M Friedland et al ldquoPhase Iand pharmacokinetic study of pegylated liposomal CKD-602 inpatients with advancedmalignanciesrdquoClinical Cancer Researchvol 15 no 4 pp 1466ndash1472 2009

[70] C Young T Schluep J Hwang and S Eliasof ldquoCRLX101(formerly IT-101)-Anovel nanopharmaceutical of camptothecinin clinical developmentrdquo Current Bioactive Compounds vol 7no 1 pp 8ndash14 2011

[71] T Hamaguchi T Doi T Eguchi-Nakajima et al ldquoPhase I studyof NK012 a novel SN-38-incorporating micellar nanoparticlein adult patients with solid tumorsrdquo Clinical Cancer Researchvol 16 no 20 pp 5058ndash5066 2010

[72] D H Palmer L S Young and V Mautner ldquoCancer gene-therapy clinical trialsrdquo Trends in Biotechnology vol 24 no 2pp 76ndash82 2006

[73] L Xu W-H Tang C-C Huang et al ldquoSystemic p53 genetherapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFvrdquoMolecular Medicine vol 7 no 10 pp723ndash734 2001

[74] K F Pirollo A Rait Q Zhou et al ldquoTumor-targeting nanocom-plex delivery of novel tumor suppressor RB94 chemosensitizesbladder carcinoma cells in vitro and in vivordquo Clinical CancerResearch vol 14 no 7 pp 2190ndash2198 2008

[75] D W Bartlett H Su I J Hildebrandt W A Weber and ME Davis ldquoImpact of tumor-specific targeting on the biodis-tribution and efficacy of siRNA nanoparticles measured bymultimodality in vivo imagingrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 104 no39 pp 15549ndash15554 2007

[76] P P Deshpande S Biswas and V P Torchilin ldquoCurrent trendsin the use of liposomes for tumor targetingrdquoNanomedicine vol8 no 9 pp 1509ndash1528 2013

[77] W T Al-Jamal and K Kostarelos ldquoLiposomes from a clinicallyestablished drug delivery system to a nanoparticle platform fortheranostic nanomedicinerdquo Accounts of Chemical Research vol44 no 10 pp 1094ndash1104 2011

[78] G Gregoriadis ldquoThe carrier potential of liposomes in biologyand medicine IIrdquo The New England Journal of Medicine vol295 no 14 pp 765ndash770 1976

[79] J L Arias ldquoLiposomes in drug delivery a patent review (2007-present)rdquo Expert Opinion onTherapeutic Patents vol 23 no 11pp 1399ndash1414 2013

[80] M R Preiss and G D Bothun ldquoStimuli-responsive liposome-nanoparticle assembliesrdquo Expert Opinion on Drug Delivery vol8 no 8 pp 1025ndash1040 2011

[81] A S Manjappa K R Chaudhari M P Venkataraju et alldquoAntibody derivatization and conjugation strategies applicationin preparation of stealth immunoliposome to target chemother-apeutics to tumorrdquo Journal of Controlled Release vol 150 no 1pp 2ndash22 2011

[82] Y Zhao S Zhang S Cui B Wang and S Zhang ldquoPeptide-based cationic liposome-mediated gene deliveryrdquo Expert Opin-ion on Drug Delivery vol 9 no 1 pp 127ndash139 2012

[83] M L Immordino F Dosio and L Cattel ldquoStealth liposomesreview of the basic science rationale and clinical applicationsexisting and potentialrdquo International Journal of Nanomedicinevol 1 no 3 pp 297ndash315 2006

[84] N K Mehra V Mishra and N K Jain ldquoReceptor-basedtargeting of therapeuticsrdquoTherapeutic Delivery vol 4 no 3 pp369ndash394 2013

[85] M Amin A Badiee and M R Jaafari ldquoImprovement ofpharmacokinetic and antitumor activity of PEGylated liposo-mal doxorubicin by targeting with N-methylated cyclic RGDpeptide in mice bearing C-26 colon carcinomasrdquo InternationalJournal of Pharmaceutics vol 458 no 2 pp 324ndash333

[86] X Liu S Ma C Dai et al ldquoAntiproliferative antiinvasiveand proapoptotic activity of folate receptor alpha-targetedliposomal doxorubicin in nonfunctional pituitary adenomacellsrdquo Endocrinology vol 154 no 4 pp 1414ndash1423 2013

[87] B Xiang D-W Dong N-Q Shi et al ldquoPSA-responsive andPSMA-mediated multifunctional liposomes for targeted ther-apy of prostate cancerrdquo Biomaterials vol 34 no 28 pp 6976ndash6991 2013

[88] ClinicalTrialsgov httpclinicaltrialsgov[89] C Brignole D Marimpietri G Pagnan et al ldquoNeuroblastoma

targeting by c-myb-selective antisense oligonucleotides entr-apped in anti-GD2 immunoliposome immune cell-mediatedanti-tumor activitiesrdquo Cancer Letters vol 228 no 1-2 pp 181ndash186 2005

[90] F Moret D Scheglmann and E Reddi ldquoFolate-targetedPEGylated liposomes improve the selectivity of PDT withmeta-tetra(hydroxyphenyl)chlorin (m-THPC)rdquo Photochemicalamp Photobiological Sciences vol 12 no 5 pp 823ndash834 2013

[91] Z Zhang and J Yao ldquoPreparation of irinotecan-loaded folate-targeted liposome for tumor targeting delivery and its antitu-mor activityrdquo AAPS PharmSciTech vol 13 no 3 pp 802ndash8102012

[92] K F Yu W Q Zhang L M Luo et al ldquoThe antitumor activityof a doxorubicin loaded iRGD-modified sterically-stabilizedliposome on B16-F10 melanoma cells in vitro and in vivoevaluationrdquo International Journal of Nanomedicine vol 8 pp2473ndash2485 2013

[93] A Wicki C Rochlitz A Orleth et al ldquoTargeting tumor-associated endothelial cells Anti-VEGFR2 immunoliposomesmediate tumor vessel disruption and inhibit tumor growthrdquoClinical Cancer Research vol 18 no 2 pp 454ndash464 2012

[94] C Ma X Li X liang K Jin J Cao and W Xu ldquoNovelbeta-dicarbonyl derivatives as inhibitors of aminopeptidase N(APN)rdquo Bioorganic amp Medicinal Chemistry Letters vol 23 no17 pp 4948ndash4952 2013

[95] A H Negussie J L Miller G Reddy S K Drake B J Woodand M R Dreher ldquoSynthesis and in vitro evaluation of cyclicNGR peptide targeted thermally sensitive liposomerdquo Journal ofControlled Release vol 143 no 2 pp 265ndash273 2010

[96] S Tan X Li Y Guo and Z Zhang ldquoLipid-enveloped hybridnanoparticles for drug deliveryrdquo Nanoscale vol 5 no 3 pp860ndash872 2013

[97] G Von Maltzahn J-H Park K Y Lin et al ldquoNanoparticlesthat communicate in vivo to amplify tumour targetingrdquo NatureMaterials vol 10 no 7 pp 545ndash552 2011

[98] W Huang J Zhang H C Dorn and C Zhang ldquoAssemblyof bio-nanoparticles for double controlled drug releaserdquo PLoSONE vol 8 no 9 Article ID e74679 2013


[99] F Karchemski D Zucker Y Barenholz and O Regev ldquoCarbonnanotubes-liposomes conjugate as a platform for drug deliveryinto cellsrdquo Journal of Controlled Release vol 160 no 2 pp 339ndash345 2012

[100] A S Narang R K Chang andM A Hussain ldquoPharmaceuticaldevelopment and regulatory considerations for nanoparticlesand nanoparticulate drug delivery systemsrdquo Journal of Pharma-ceutical Sciences vol 102 no 11 pp 3867ndash3882 2013

[101] R Duncan ldquoPolymer conjugates as anticancer nanomedicinesrdquoNature Reviews Cancer vol 6 no 9 pp 688ndash701 2006

[102] S S Banerjee N Aher R Patil and J Khandare ldquoPoly(ethyleneglycol)-prodrug conjugates concept design and applicationsrdquoJournal of Drug Delivery vol 2012 Article ID 103973 17 pages2012

[103] H Sah L A Thoma H R Desu E Sah and G CWood ldquoConcepts and practices used to develop functionalPLGA-based nanoparticulate systemsrdquo International Journal ofNanomedicine vol 8 pp 747ndash765 2013

[104] F Danhier E Ansorena J M Silva R Coco A Le Bretonand V Preat ldquoPLGA-based nanoparticles an overview ofbiomedical applicationsrdquo Journal of Controlled Release vol 161no 2 pp 505ndash522 2012

[105] S Acharya and S K Sahoo ldquoPLGA nanoparticles containingvarious anticancer agents and tumour delivery by EPR effectrdquoAdvancedDrugDelivery Reviews vol 63 no 3 pp 170ndash183 2011

[106] F Danhier N Lecouturier B Vroman et al ldquoPaclitaxel-loadedPEGylated PLGA-based nanoparticles in vitro and in vivoevaluationrdquo Journal of Controlled Release vol 133 no 1 pp 11ndash17 2009

[107] J Liang Y Luo and H Zhao ldquoSynthetic biology puttingsynthesis into biologyrdquo Wiley Interdisciplinary Reviews vol 3no 1 pp 7ndash20 2011

[108] W Hasan K Chu A Gullapalli et al ldquoDelivery of multiplesiRNAs using lipid-coated PLGA nanoparticles for treatment ofprostate cancerrdquo Nano Letters vol 12 no 1 pp 287ndash292 2012

[109] C Chittasupho S-X Xie A Baoum T Yakovleva T J Siahaanand C J Berkland ldquoICAM-1 targeting of doxorubicin-loadedPLGA nanoparticles to lung epithelial cellsrdquo European Journalof Pharmaceutical Sciences vol 37 no 2 pp 141ndash150 2009

[110] C Liang Y Yang Y Ling Y Huang T Li and X Li ldquoImprovedtherapeutic effect of folate-decorated PLGA-PEG nanoparticlesfor endometrial carcinomardquo Bioorganic and Medicinal Chem-istry vol 19 no 13 pp 4057ndash4066 2011

[111] H Zhao and L Y L Yung ldquoAddition of TPGS to folate-conjugated polymer micelles for selective tumor targetingrdquoJournal of Biomedical Materials Research - Part A vol 91 no2 pp 505ndash518 2009

[112] R M Taylor V Severns D C Brown M Bisoffi and L OSillerud ldquoProstate cancer targeting motifs Expression of 120572v1205733neurotensin receptor 1 prostate specificmembrane antigen andprostate stem cell antigen in human prostate cancer cell linesand xenograftsrdquo Prostate vol 72 no 5 pp 523ndash532 2012

[113] S Dhar F X Gu R Langer O C Farokhza and S JLippard ldquoTargeted delivery of cisplatin to prostate cancercells by aptamer functionalized Pt(IV) prodrug-PLGA - PEGnanoparticlesrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 105 no 45 pp 17356ndash173612008

[114] F Danhier V Pourcelle J Marchand-Brynaert C Jerome OFeron and V Preat ldquoTargeting of tumor endothelium by RGD-grafted PLGA-nanoparticlesrdquoMethods in Enzymology vol 508pp 157ndash175 2012

[115] R Hassert P G Hoffmeister M Pagel M Hacker M Schulz-Siegmund and A G Beck-Sickinger ldquoOn-resin synthesis ofan acylated and fluorescence-labeled cyclic integrin ligandfor modification of poly(lactic-co-glycolic acid)rdquo Chemistry ampBiodiversity vol 9 no 11 pp 2648ndash2658 2012

[116] A Aravind P Jeyamohan R Nair et al ldquoAS1411 aptamer taggedPLGA-lecithin-PEG nanoparticles for tumor cell targeting anddrug deliveryrdquo Biotechnology and Bioengineering vol 109 no 11pp 2920ndash2931 2012

[117] J Guo X Gao L Su et al ldquoAptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug deliveryrdquoBiomaterials vol 32 no 31 pp 8010ndash8020 2011

[118] B Fadeel ldquoClear and present danger Engineered nanoparticlesand the immune systemrdquo Swiss Medical Weekly vol 142 ArticleID w13609 2012

[119] R Becker C Dembek L AWhite and L P Garrison ldquoThe costoffsets and cost-effectiveness associated with pegylated drugs areview of the literaturerdquo Expert Review of Pharmacoeconomicsamp Outcomes Research vol 12 no 6 pp 775ndash793 2012

[120] S Kommareddy S B Tiwari and M M Amiji ldquoLong-circulating polymeric nanovectors for tumor-selective genedeliveryrdquo Technology in Cancer Research and Treatment vol 4no 6 pp 615ndash625 2005

[121] S Raha T Paunesku and G Woloschak ldquoPeptide-mediatedcancer targeting of nanoconjugatesrdquo Wiley InterdisciplinaryReviews Nanomedicine and Nanobiotechnology vol 3 no 3 pp269ndash281 2011

[122] E Segal and R Satchi-Fainaro ldquoDesign and development ofpolymer conjugates as anti-angiogenic agentsrdquo Advanced DrugDelivery Reviews vol 61 no 13 pp 1159ndash1176 2009

[123] Y Xiong W Jiang Y Shen et al ldquoA Poly(120574 l-glutamic acid)-citric acid based nanoconjugate for cisplatin deliveryrdquo Biomate-rials vol 33 no 29 pp 7182ndash7193 2012

[124] X Zhao H Li and R J Lee ldquoTargeted drug delivery via folatereceptorsrdquo Expert Opinion on Drug Delivery vol 5 no 3 pp309ndash319 2008

[125] X B Zhao and R J Lee ldquoTumor-selective targeted deliveryof genes and antisense oligodeoxyribonucleotides via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 56 no 8 pp1193ndash1204 2004

[126] L Teng J Xie and R J Lee ldquoClinical translation of folatereceptor-targeted therapeuticsrdquo Expert Opinion on Drug Deliv-ery vol 9 no 8 pp 901ndash908 2012

[127] G L Zwicke G A Mansoori and C J Jeffery ldquoUtilizing thefolate receptor for active targeting of cancer nanotherapeuticsrdquoNano Reviews vol 3 pp 18496ndash18506 2012

[128] XMing KCarver and LWu ldquoAlbumin-based nanoconjugatesfor targeted delivery of therapeutic oligonucleotidesrdquo Biomate-rials vol 34 no 32 pp 7939ndash7949 2013

[129] R K Mittapalli X Liu C E Adkins et al ldquoPaclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclin-ical brain metastases of breast cancer modelrdquoMolecular CancerTherapeutics vol 12 no 11 pp 2389ndash2399 2013

[130] C Boyer M R Whittaker V Bulmus J Liu and T PDavis ldquoThe design and utility of polymer-stabilized iron-oxide nanoparticles for nanomedicine applicationsrdquo NPG AsiaMaterials vol 2 no 1 pp 23ndash30 2010

[131] B Polyak andG Friedman ldquoMagnetic targeting for site-specificdrug delivery Applications and clinical potentialrdquo Expert Opin-ion on Drug Delivery vol 6 no 1 pp 53ndash70 2009


[132] J Meng J Fan G Galiana et al ldquoLHRH-functionalizedsuperparamagnetic iron oxide nanoparticles for breast cancertargeting and contrast enhancement in MRIrdquoMaterials Scienceand Engineering C vol 29 no 4 pp 1467ndash1479 2009

[133] M K Yu Y Y Jeong J Park et al ldquoDrug-loaded superparamag-netic iron oxide nanoparticles for combined cancer imaging andtherapy in vivordquoAngewandteChemie - International Edition vol47 no 29 pp 5362ndash5365 2008

[134] N Kohler C Sun J Wang and M Zhang ldquoMethotrexate-modified superparamagnetic nanoparticles and their intracel-lular uptake into human cancer cellsrdquo Langmuir vol 21 no 19pp 8858ndash8864 2005

[135] A Figuerola R Di Corato L Manna and T Pellegrino ldquoFromiron oxide nanoparticles towards advanced iron-based inor-ganic materials designed for biomedical applicationsrdquo Pharma-cological Research vol 62 no 2 pp 126ndash143 2010

[136] G Shipp ldquoUltrasensitive measurement of protein and nucleicacid biomarkers for earlier disease detection and more effectivetherapiesrdquoBiotechnologyHealthcare Journal vol 3 no 2 pp 35ndash40 2006

[137] G Peng U Tisch O Adams et al ldquoDiagnosing lung cancer inexhaled breath using gold nanoparticlesrdquo Nature Nanotechnol-ogy vol 4 no 10 pp 669ndash673 2009

[138] C SThaxton R Elghanian A DThomas et al ldquoNanoparticle-based bio-barcode assay redefines ldquoundetectablerdquo PSA and bio-chemical recurrence after radical prostatectomyrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 44 pp 18437ndash18442 2009

[139] V Singh D Joung L Zhai S Das S I Khondaker and S SealldquoGraphene based materials past present and futurerdquo Progressin Materials Science vol 56 no 8 pp 1178ndash1271 2011

[140] C Cha S R Shin N Annabi M R Dokmeci and A Kha-demhosseini ldquoCarbon-based nanomaterials multifunctionalmaterials for biomedical engineeringrdquo ACS Nano vol 7 no 4pp 2891ndash2897 2013

[141] A Biswas I S Bayer A S Biris T Wang E Dervishiand F Faupel ldquoAdvances in top-down and bottom-up surfacenanofabrication techniques applications amp future prospectsrdquoAdvances in Colloid and Interface Science vol 170 no 1-2 pp2ndash27 2012

[142] P Sharma V Bhalla E S Prasad V Dravid G Shekhawat andC R Suri ldquoEnhancing grapheneCNT based electrochemicaldetection using magneto-nanobioprobesrdquo Scientific Reportsvol 2 pp 877ndash883 2012

[143] K Mallick and A M Strydom ldquoBiophilic carbon nanotubesrdquoColloids and Surfaces B vol 105 pp 310ndash318 2013

[144] B Kateb M Van Handel L Zhang M J Bronikowski HManohara and B Badie ldquoInternalization of MWCNTs bymicroglia possible application in immunotherapy of braintumorsrdquo NeuroImage vol 37 no 1 pp S9ndashS17 2007

[145] B Kateb K Chiu K L Black et al ldquoNanoplatforms forconstructing new approaches to cancer treatment imaging anddrug deliveryWhat should be the policyrdquoNeuroImage vol 54supplement 1 pp S106ndashS124 2011

[146] A Bianco K Kostarelos CD Partidos andM Prato ldquoBiomed-ical applications of functionalised carbon nanotubesrdquo ChemicalCommunications no 5 pp 571ndash577 2005

[147] A Ruggiero C H Villa E Bander et al ldquoParadoxical glomeru-lar filtration of carbon nanotubesrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 107 no27 pp 12369ndash12374 2010

[148] Z Liu W Cai L He et al ldquoin vivo biodistribution and highlyefficient tumour targeting of carbon nanotubes in micerdquoNatureNanotechnology vol 2 no 1 pp 47ndash52 2007

[149] C Chung Y-K Kim D Shin S-R Ryoo B H Hong andD-H Min ldquoBiomedical applications of graphene and grapheneoxiderdquo Accounts of Chemical Research vol 46 no 10 pp 2211ndash2224 2013

[150] M Cai D Thorpe D H Adamsonb and H C SchnieppldquoMethods of graphite exfoliationrdquo Journal of Materials Chem-istry vol 22 no 48 pp 24992ndash25002 2012

[151] S Z Butler SMHollen L Cao et al ldquoProgress challenges andopportunities in two-dimensional materials beyond graphenerdquoACS Nano vol 7 no 4 pp 2898ndash2926 2013

[152] H Shen L Zhang M Liu and Z Zhang ldquoBiomedical applica-tions of graphenerdquoTheranostics vol 2 no 3 pp 283ndash294 2012

[153] D R Dreyer S Park C W Bielawski and R S Ruoff ldquoThechemistry of graphene oxiderdquoChemical Society Reviews vol 39no 1 pp 228ndash240 2010

[154] K Yang L Feng X Shi and Z Liu ldquoNano-graphenein biomedicine theranostic applicationsrdquo Chemical SocietyReviews vol 42 no 2 pp 530ndash547 2013

[155] S Shi K Yang H Hong et al ldquoTumor vasculature targetingand imaging in living mice with reduced graphene oxiderdquoBiomaterials vol 34 no 12 pp 3002ndash3009 2013

[156] K Yang S Zhang G Zhang X Sun S-T Lee and Z LiuldquoGraphene inmice ultrahigh in vivo tumor uptake and efficientphotothermal therapyrdquo Nano Letters vol 10 no 9 pp 3318ndash3323 2010

[157] S Svenson and D A Tomalia ldquoDendrimers in biomedicalapplications reflections on the fieldrdquo Advanced Drug DeliveryReviews vol 57 no 15 pp 2106ndash2129 2005

[158] A R Menjoge R M Kannan and D A Tomalia ldquoDendrimer-based drug and imaging conjugates design considerations fornanomedical applicationsrdquoDrug Discovery Today vol 15 no 5-6 pp 171ndash185 2010

[159] S H Medina and M E H El-Sayed ldquoDendrimers as carriersfor delivery of chemotherapeutic agentsrdquoChemical Reviews vol109 no 7 pp 3141ndash3157 2009

[160] Q Xu C-HWang andDW Pack ldquoPolymeric carriers for genedelivery chitosan and poly(amidoamine) dendrimersrdquo CurrentPharmaceutical Design vol 16 no 21 pp 2350ndash2368 2010

[161] R Huang L Han J Li et al ldquoChlorotoxin-modified macro-molecular contrast agent for MRI tumor diagnosisrdquo Biomate-rials vol 32 no 22 pp 5177ndash5186 2011

[162] M T Morgan Y Nakanishi D J Kroll et al ldquoDendrimer-encapsulated camptothecins increased solubility cellularuptake and cellular retention affords enhanced anticanceractivity in vitrordquo Cancer Research vol 66 no 24 pp 11913ndash11921 2006

[163] F Wang X Cai Y Su et al ldquoReducing cytotoxicity whileimproving anti-cancer drug loading capacity of polypropylen-imine dendrimers by surface acetylationrdquo Acta Biomaterialiavol 8 no 12 pp 4304ndash4313

[164] A Carlmark E Malmstrom and M Malkoch ldquoDendriticarchitectures based on bis-MPA functional polymeric scaffoldsfor application-driven researchrdquo Chemical Society Reviews vol42 no 13 pp 5858ndash5879 2013

[165] S Svenson and A S Chauhan ldquoDendrimers for enhanced drugsolubilizationrdquo Nanomedicine vol 3 no 5 pp 679ndash702 2008

[166] S Svenson ldquoDendrimers as versatile platform in drug deliveryapplicationsrdquo European Journal of Pharmaceutics and Biophar-maceutics vol 71 no 3 pp 445ndash462 2009


[167] B Yu H C Tai W Xue L J Lee and R J Lee ldquoReceptor-targeted nanocarriers for therapeutic delivery to cancerrdquoMolec-ular Membrane Biology vol 27 no 7 pp 286ndash298 2010

[168] P Kesharwani VGajbhiye andNK Jain ldquoA reviewof nanocar-riers for the delivery of small interfering RNArdquo Biomaterialsvol 33 no 29 pp 7138ndash7150 2012

[169] M Sarikaya C Tamerler A K-Y Jen K Schulten andF Baneyx ldquoMolecular biomimetics nanotechnology throughbiologyrdquo Nature Materials vol 2 no 9 pp 577ndash585 2003

[170] R Farr D S Choi and S W Lee ldquoPhage-based nanomaterialsfor biomedical applicationsrdquo Acta Biomaterialia 2013

[171] N F Steinmetz ldquoViral nanoparticles as platforms for next-generation therapeutics and imaging devicesrdquo Nanomedicinevol 6 no 5 pp 634ndash641 2010

[172] E M Plummer and M Manchester ldquoViral nanoparticlesand virus-like particles platforms for contemporary vaccinedesignrdquo Wiley Interdisciplinary Reviews vol 3 no 2 pp 174ndash196 2011

[173] M-A Poul and J D Marks ldquoTargeted gene delivery to mam-malian cells by filamentous bacteriophagerdquo Journal ofMolecularBiology vol 288 no 2 pp 203ndash211 1999

[174] D Frenkel and B Solomon ldquoFilamentous phage as vector-mediated antibody delivery to the brainrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 8 pp 5675ndash5679 2002

[175] T Nishimoto K Yoshida Y Miura et al ldquoOncolytic virustherapy for pancreatic cancer using the adenovirus librarydisplaying random peptides on the fiber knobrdquo Gene Therapyvol 16 no 5 pp 669ndash680 2009

[176] S E Luria ldquoBacteriophage an essay on virus reproductionrdquoScience vol 111 no 2889 pp 507ndash511 1950

[177] S K Straus W R P Scott M F Symmons and D A MarvinldquoOn the structures of filamentous bacteriophage Ff (fd f1M13)rdquoEuropean Biophysics Journal vol 37 no 4 pp 521ndash527 2008

[178] K Valegard L Liljas K Fridborg and T Unge ldquoThe three-dimensional structure of the bacterial virus MS2rdquo Nature vol345 no 6270 pp 36ndash41 1990

[179] A Merzlyak S Indrakanti and S-W Lee ldquoGenetically engi-neered nanofiber-like viruses for tissue regenerating materialsrdquoNano Letters vol 9 no 2 pp 846ndash852 2009

[180] S F Parmley and G P Smith ldquoAntibody-selectable filamentousfd phage vectors affinity purification of target genesrdquoGene vol73 no 2 pp 305ndash318 1988

[181] J K Scott and G P Smith ldquoSearching for peptide ligands withan epitope libraryrdquo Science vol 249 no 4967 pp 386ndash390 1990

[182] G P Smith and V A Petrenko ldquoPhage displayrdquo ChemicalReviews vol 97 no 2 pp 391ndash410 1997

[183] Z M Carrico D W Romanini R A Mehl and M B FrancisldquoOxidative coupling of peptides to a virus capsid containingunnatural amino acidsrdquo Chemical Communications no 10 pp1205ndash1207 2008

[184] R A Miller A D Presley and M B Francis ldquoSelf-assemblinglight-harvesting systems from synthetically modified tobaccomosaic virus coat proteinsrdquo Journal of the American ChemicalSociety vol 129 no 11 pp 3104ndash3109 2007

[185] N Stephanopoulos Z M Carrico and M B FrancisldquoNanoscale integration of sensitizing chromophores and por-phyrins with bacteriophage MS2rdquo Angewandte Chemie vol 48no 50 pp 9498ndash9502 2009

[186] T L Schlick Z Ding E W Kovacs and M B Francis ldquoDual-surface modification of the tobaccomosaic virusrdquo Journal of theAmerican Chemical Society vol 127 no 11 pp 3718ndash3723 2005

[187] G P Smith ldquoFilamentous fusion phage novel expressionvectors that display cloned antigens on the virion surfacerdquoScience vol 228 no 4705 pp 1315ndash1317 1985

[188] R Pasqualini and E Ruoslahti ldquoOrgan targeting in vivo usingphage display peptide librariesrdquo Nature vol 380 no 6572 pp364ndash366 1996

[189] W Arap R Pasqualini and E Ruoslahti ldquoCancer treatment bytargeted drug delivery to tumor vasculature in a mouse modelrdquoScience vol 279 no 5349 pp 377ndash380 1998

[190] D N Krag G S Shukla G-P Shen et al ldquoSelection of tumor-binding ligands in cancer patients with phage display librariesrdquoCancer Research vol 66 no 15 pp 7724ndash7733 2006

[191] T J Dickerson and K D Janda ldquoRecent advances for the treat-ment of cocaine abuse central nervous system immunophar-macotherapyrdquo AAPS Journal vol 7 no 3 pp E579ndashE586 2005

[192] I Yacoby H Bar and I Benhar ldquoTargeted drug-carryingbacteriophages as antibacterial nanomedicinesrdquo AntimicrobialAgents and Chemotherapy vol 51 no 6 pp 2156ndash2163 2007


[194] A Hajitou M Trepel C E Lilley et al ldquoA hybrid vector forligand-directed tumor targeting and molecular imagingrdquo Cellvol 125 no 2 pp 385ndash398 2006

[195] M E Martin and K G Rice ldquoPeptide-guided gene deliveryrdquoAAPS Journal vol 9 no 1 pp E18ndashE29 2007

[196] D Larocca A Witte W Johnson G F Pierce and A BairdldquoTargeting bacteriophage to mammalian cell surface receptorsfor gene deliveryrdquoHumanGeneTherapy vol 9 no 16 pp 2393ndash2399 1998

[197] J D Mount T I Samoylova N E Morrison N R Cox H JBaker and V A Petrenko ldquoCell targeted phagemid rescued bypreselected landscape phagerdquo Gene vol 341 no 1-2 pp 59ndash652004

[198] S Piersanti G Cherubini Y Martina et al ldquoMammaliancell transduction and internalization properties of 120582 phagesdisplaying the full-length adenoviral penton base or its centraldomainrdquo Journal of Molecular Medicine vol 82 no 7 pp 467ndash476 2004

[199] S L Hart A M Knight R P Harbottle et al ldquoCell binding andinternalization by filamentous phage displaying a cyclic Arg-Gly-Asp-containing peptiderdquo Journal of Biological Chemistryvol 269 no 17 pp 12468ndash12474 1994

[200] M A Burg K Jensen-Pergakes A M Gonzalez P RaveyA Baird and D Larocca ldquoEnhanced phagemid particlegene transfer in camptothecin-treated carcinoma cellsrdquo CancerResearch vol 62 no 4 pp 977ndash981 2002

[201] Y Seow and M J Wood ldquoBiological gene delivery vehiclesbeyond viral vectorsrdquoMolecular Therapy vol 17 no 5 pp 767ndash777 2009

[202] D Ghosh Y Lee S Thomas et al ldquoM13-templated magneticnanoparticles for targeted in vivo imaging of prostate cancerrdquoNature Nanotechnology vol 7 no 10 pp 677ndash682 2012

[203] M S Muthu and B Wilson ldquoMultifunctional radionano-medicine a novel nanoplatform for cancer imaging and ther-apyrdquo Nanomedicine vol 5 no 2 pp 169ndash171 2010

[204] J W Bulte and M Modo Eds Nanoparticles in BiomedicalImaging Emerging Technologies andApplications Springer NewYork NY USA 2007


[205] D Janczewski Y Zhang G K Das et al ldquoBimodal magnetic-fluorescent probes for bioimagingrdquo Microscopy Research andTechnique vol 74 no 7 pp 563ndash576 2011

[206] P A Jarzyna A Gianella T Skajaa et al ldquoMultifunctionalimaging nanoprobesrdquoWiley Interdisciplinary Reviews vol 2 no2 pp 138ndash150 2010

[207] ldquoNanoparticles in biomedical imaging emerging technologiesand applicationsrdquo in Fundamental Biomedical Technologies MM J M Jeff andWM Bulte Eds vol 102 Springer New YorkNY USA 2008

[208] M T McMahon A A Gilad M A DeLiso S M CromerBerman JWM Bulte and P CMVan Zijl ldquoNew ldquomulticolorrdquopolypeptide diamagnetic chemical exchange saturation transfer(DIACEST) contrast agents for MRIrdquo Magnetic Resonance inMedicine vol 60 no 4 pp 803ndash812 2008

[209] H Cabral Y Matsumoto K Mizuno et al ldquoAccumulation ofsub-100 nm polymeric micelles in poorly permeable tumoursdepends on sizerdquoNature Nanotechnology vol 6 no 12 pp 815ndash823 2011

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of



CeramicsJournal of


CompositesJournal of

NanoparticlesJournal of



International Journal of

Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


administration of small molecules genes and peptides withimprovement of given in vivo behavior [8ndash10] Figure 1shows the schematic diagrams of targeted delivery systemswith nanoplatforms such as liposome polymeric micellenanoconjugate gold nanoparticle carbon nanotube den-drimer and phage-based nanoplatform Several characteris-tics of an ideal tumor-targeted nanomedicine with nanoplat-forms are presented for translational research of ideal anti-cancer therapeutics as follows (1) increase of drug localiza-tion into the tumor by passive targeting or active targeting(2) decrease of drug localization in sensitive nontargetedand normal tissues (3) minimal drug leakage during transitto the target (4) prevention of degradation and prematureclearance of the drug (5) retainment of the drug at thetarget site during the desired period (6) facilitation of cellularuptake and intracellular trafficking and (7) biocompatibilityand biodegradability of nanoplatforms [10] Table 1 illustratesthe recently developed nanoplatforms for cancer targetingin preclinical studies We introduce recent studies of tar-geted anticancer system in the part of ldquorecently developednanoplatforms for cancer targeting in preclinical studiesrdquo

For successful translational research of nanoplatformsin anticancer therapy Doxil is an FDA approved drug forthe treatment of ovarian cancer which is a long-actingpegylated liposomal formulation of doxorubicin [11 12] Thisproduct is based on a study of liposomal drug deliverysystems for over four decades overcoming the limitationsof anticancer drug and liposomes such as poor stabilityand reproducibility [13 14] It is one of the successful casesfor the development of nanomedicines offering significantimprovements over doxorubicin alone in clinical useWe dealwith the translational research of nanomedicines in Table 2and introduce the anticancer drugs approved by FDA inTable 3 Based on the ideal characteristics of nanoplatformsthey can be designed for the following (1) sustained releaseof the drug (2) passive accumulation of the tumor tissue (3)ligand-based targeting of cell surface antigens or receptorswith the modulation of endosomal uptake and membranedisruption (4) drug release into the cytoplasm and (5)protection from enzymatic degradation [15 16] Additionallyin this review we demonstrate the applications of targeteddelivery systems from the cells to the clinics for anticancertherapy diagnostics nanoimaging bimodal imaging andreal-time intraoperative imaging

2 Mechanism of CancerTargeting by Nanoplatforms

Many nanobiomaterial-based platforms have been designedand evaluated for drug targeting to cancers as shown inFigure 2 Most of these platforms are ldquopassive targetingrdquoconcepts to improve the circulation time of the conjugated orencapsulated therapeutic drug such as liposomes polymersmicelles and nanoparticles Solid tumors have blood vesselswith enhanced vascular permeability and a lack of functionallymphatics which allow extravasation of carrier materialswith sizes of up to several hundreds of nanometers and

are unable to eliminate extravasated nanomaterials Fromthe several reports this EPR effect was shown even for theparticles size of 1-2120583m (eg Lactobacillus sp Salmonella spetc) which could make the particles accumulated in tumortissues [17 18] Therefore long-circulating nanomedicinesare able to be accumulated in tumors over time based ona mechanism known as the enhanced permeability andretention (EPR) effect [19 20] The EPR effect is a uniquephenomenon of solid tumors related to their anatomi-cal and pathophysiological differences from normal tissuesand is the most important strategy to improve the deliv-ery of therapeutic agents to tumors for anticancer drugdevelopment Examples of passively targeted nanoplatformsapproved for clinical use are Doxil (Caelyx in Europe pegy-lated liposomal doxorubicin) DaunoXome (nonpegylatedliposomal daunorubicin) DepoCyt (nonpegylated liposomalcytarabine) Myocet (nonpegylated liposomal doxorubicin)Oncaspar (pegylated L-asparaginase) Abraxane (albumin-based paclitaxel) and Genexol-PM (paclitaxel-containingpolymeric micelles approved in Korea) In particular Doxilis a pegylated liposome-based doxorubicin-loaded anti-cancer drug which is FDA approved for the treatmentof ovarian cancer as mentioned above This drug has asevere cardiotoxicity although it overcomes poor stabilityand reproducibility of liposomes and improves a biodis-tribution of doxorubicin in tumor tissues by EPR effectIn addition Abraxane is a Cremophor EL-free albumin-bound paclitaxel It reduced Cremophor EL-associated sideeffects of Taxol such as severe anaphylactoid hypersensitivityreactions hyperlipidaemia abnormal lipoprotein patternsaggregation of erythrocytes and peripheral neuropathy [21]Next-generation nanomedicines for anticancer therapy aredeveloping alternative approaches with recently developednanoplatforms minimizing side effects of surfactants informulations and targeting tumor tissues Several additionalpassively tumor-targeted nanomedicines are currently inclinical trials (Table 2) and many other ones are in early andlate-stage preclinical development [9 22ndash25]

On the other hand ldquoactive targetingrdquo strategy indicatesthe use of targeting ligands like antibodies and peptideswhich are attached to drugs and drug delivery nanoplatformsfor binding to receptor expressed at the target site In thisstrategy active targeting systems with ligands and antibodiesneed to be accumulated first in tumor tissues by EPReffect and then active targeting could be achieved Targetingligands for actively targeting nanomedicines are improvingcellular internalization via endocytosis-prone surface recep-tors such as folate [26] galactosamine [27] EGF [28] andtransferrin [29] To date targeting techniques for activetargeting are advanced at the preclinical level however onlyantibody-based nanomedicines have been approved for clin-ical use (Tables 2 and 3) Zevalin (CD20-targeted 90Yttrium-ibritumomab tiuxetan) Bexxar (CD20-targeted iodine-131tositumomab) Ontak (CD25-targeted diphtheria toxin-IL-2 fusion protein) and Mylotarg (CD33-targetd gemtuzumaboxogamicin) have been successfully used for non-Hodgkinrsquoslymphoma T-cell lymphoma and acutemyeloid leukemia Inaddition it has necessitated the use of peptides to enable the


(a) (b) (c) (d)

(e) (f) (g)

Targeting ligand

Au












Table1Re

centlydevelopednano

platform

sfor

cancer

targetingin

preclin

icalstu

dies

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Lipo

somes

Doxorub

icin

108

CyclicA

sn-G

ly-Arg

(cNGR)

peptidesCD13

and

aminop

eptid

aseN

cNGRdecorated

lysolip

id-con

tainingtemperature

sensitive

liposom

es

Hum

anfib

rosarcom

a(H

T-1080)

invitro

bind

ingstu

dy[95]

Lipo

somes

inorganic

nano

particles

(goldnano

rods

irono

xide

nano

worms)

Doxorub

icin

55

Atrun

cated

tumor-ta

rgeted

human


RGD)toindu

cecoagulationon

bind

ingto


toheatspecifically

directed

coagulation-cascade

activ

ationin

tumou

rs


odules

(PEG

-decorated

gold

nano

rods

tumor-ta

rgeted

trun

catedtissue

factor

proteins)thattarget

tumorsa

ndthen

locally

activ

ate

thec

oagu

latio

ncascadeto

broadcasttum

orlocatio

nto


nano


carryad

iagn

ostic

ortherapeutic

cargo(iron

oxiden

anow

orms

doxorubicin-loaded

liposom

es)

Invivo

MDA-

MB-435

xeno

graft

tumors

ivinjectio

n[97]

Lipo

somes

carbon

nano

tubes

Paclitaxel

164

anti-ErBb

2(H

er2)

mAb

Each

nano

horn

encapsulated

with

inon

eimmun

oliposom

eform

ulated

with

PEGand

thermallysta

blea

ndpH

sensitive

phosph

olipidsfor

pHsensitive

andprolon

gedreleaseo

fpaclitaxel

SK-BR-3andBT

-20

breastcancer

cells

invitro

cytotoxicity

[98]

Polymericnano

particles

siRNA

80times320

mdash

Catio

niclipid-coatedPL

GA

nano

particlesau

niqu

esoft

litho

graphy

particlemolding


nonw

ettin

gtemplatesP

RINT)

Invitro

prostate

cancer

celllin

es[108]

Polymericmicelles

12-D

iaminocyclohexane-

platinum

(II)(D

ACHPt)(thep

arent

complex

ofoxaliplatin

)30

mdash

Long

-circ

ulatingdrug-lo

aded

polymericmicellese

nhancing

tumou

rpermeabilitywith

aTG

F120573inhibitor

Poorlyperm

eable

pancreatictumorsin

them

icem

odel(C

26or

BxPC

3tumors)

ivinjectio

n

[209]

Nanocon

jugates

Splice-sw

itching

oligon

ucleotides

(SSO

s)(pho

spho

rodiam

idate

morph

olinooligom

er(PMO))

13

RGDin

tegrin120572]1205733a

cell

surfa

ceglycop

rotein

thatis

preferentia

llyexpressed

inangiogenicendo

thelia

Album

in-based

nano

conjugates

with


which

ares

mallhigh

lyspecificand

noncytotoxic

Tumor

spheroidso

fA375GFP

cell

tumor

spheroid

study

usingA375GFP

cells

toconfi

rmtheu

ptake

andpenetrationof

nano

conjugates

inthree-dimensio

nal

(3D)c

ulture

[128]


ble1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Paclitaxel

2-3


cid

(HA)CD

44

Paclitaxel-u

ltrasmallH

A(3ndash5

kDa)

nano

conjugates

internalized

viaC

D44

receptor-m

ediatedendo

cytosis

which

allowed

paclitaxelto

bypasstheP

-glycoprotein-

mediatedeffl

uxon

thes

urface

ofcancer

cells

Brainmetastasis

ofbreastcancer

using

MDA-

MB-231Br

breastcancer

cells

ivinjectio

n

[129]

Goldnano

particles

Chem

iresistorsbasedon

functio

nalized

gold

nano

particlesin

combinatio

nwith

patte

rnrecogn

ition

metho

ds

5mdash

Asensor

arrayforb

reathtesting

ofexhaledbreath

inlung

cancer

patie

nts

Ano

ninvasive

diagno

stictoolfor

lung

cancer

invitro

array

[137]

Goldnano

particles

magnetic

microparticles

AnassayforP

SAdetectionwith

gold

nano

particlesb

ased

onthe

PSA-

specificA

bsandshortD

NA

sequ

ences(barcod

es)

30Prostate-specific

antig

en(PSA

)

Magnetic

microparticles

conjug

ated

with

PSA-

specific

antib

odiestoextracttrace

amou

ntso

fthe

targetanalyte

(PSA

)inserum

samples

from

patie

ntsa

ndgold

nano

particles

with

PSA-

specifica

ntibod

iesa

ndshortD

NAsequ

ences(the

barcod

es)atta

ched

todetectthis

analyte

Anultrasensitive

assayforp

rosta

tecancer

invitro

barcod

earray

[138]

Carbon

nano

tube

Sing

le-w

alledcarbon

nano

tube

(SWCN

T)with

fluorescence

labelling

200ndash

300

mdashBiod

istrib

utionandexam

ination

ofglom

erular

filtrationin

kidn

ey

NIR

fluorescence

imagingdynamic

PETim

aging

invitro

(HK-

2cells

atthetranswell)

invivo

(mice

NCr

nunu

)ivinjectio

n

[147]

Water

solublec

arbo

nnano

tubes

functio

nalized

with

PEGradio

labels

andRG

Dpeptide

1ndash5(diameter)

100ndash

300(le

ngth)

RGDin

tegrins120572

]1205733

RGD-pegylated

SWCN

Ts

radio-labelledSW

CNTs

U87MGhu

man

glioblastomaa

ndHT-29

human

colorectalcancer

cell

linesU

87MGand

HT-29

tumou

rxeno

graft

mod

elsfor

biod

istrib

ution(PET

)ivinjectio

n

[148]

Graph

ene

Nanograph

enes

heet(N

GS)

for

phototherm

altherapy(PTT

)10ndash50

mdashSix-armed

PEG-N

GSwith

fluorescent

labelin

g

4T1b

earin

gBa

lbc

miceKB

andU87MG

xeno

graft

mod

els

PTT

ivinjectio

n

[155]


Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage


tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL


cidRG


(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




(a) (b) (c) (d)

(e) (f) (g)

Targeting ligand

Au












Table1Re

centlydevelopednano

platform

sfor

cancer

targetingin

preclin

icalstu

dies

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Lipo

somes

Doxorub

icin

108

CyclicA

sn-G

ly-Arg

(cNGR)

peptidesCD13

and

aminop

eptid

aseN

cNGRdecorated

lysolip

id-con

tainingtemperature

sensitive

liposom

es

Hum

anfib

rosarcom

a(H

T-1080)

invitro

bind

ingstu

dy[95]

Lipo

somes

inorganic

nano

particles

(goldnano

rods

irono

xide

nano

worms)

Doxorub

icin

55

Atrun

cated

tumor-ta

rgeted

human


RGD)toindu

cecoagulationon

bind

ingto


toheatspecifically

directed

coagulation-cascade

activ

ationin

tumou

rs


odules

(PEG

-decorated

gold

nano

rods

tumor-ta

rgeted

trun

catedtissue

factor

proteins)thattarget

tumorsa

ndthen

locally

activ

ate

thec

oagu

latio

ncascadeto

broadcasttum

orlocatio

nto


nano


carryad

iagn

ostic

ortherapeutic

cargo(iron

oxiden

anow

orms

doxorubicin-loaded

liposom

es)

Invivo

MDA-

MB-435

xeno

graft

tumors

ivinjectio

n[97]

Lipo

somes

carbon

nano

tubes

Paclitaxel

164

anti-ErBb

2(H

er2)

mAb

Each

nano

horn

encapsulated

with

inon

eimmun

oliposom

eform

ulated

with

PEGand

thermallysta

blea

ndpH

sensitive

phosph

olipidsfor

pHsensitive

andprolon

gedreleaseo

fpaclitaxel

SK-BR-3andBT

-20

breastcancer

cells

invitro

cytotoxicity

[98]

Polymericnano

particles

siRNA

80times320

mdash

Catio

niclipid-coatedPL

GA

nano

particlesau

niqu

esoft

litho

graphy

particlemolding


nonw

ettin

gtemplatesP

RINT)

Invitro

prostate

cancer

celllin

es[108]

Polymericmicelles

12-D

iaminocyclohexane-

platinum

(II)(D

ACHPt)(thep

arent

complex

ofoxaliplatin

)30

mdash

Long

-circ

ulatingdrug-lo

aded

polymericmicellese

nhancing

tumou

rpermeabilitywith

aTG

F120573inhibitor

Poorlyperm

eable

pancreatictumorsin

them

icem

odel(C

26or

BxPC

3tumors)

ivinjectio

n

[209]

Nanocon

jugates

Splice-sw

itching

oligon

ucleotides

(SSO

s)(pho

spho

rodiam

idate

morph

olinooligom

er(PMO))

13

RGDin

tegrin120572]1205733a

cell

surfa

ceglycop

rotein

thatis

preferentia

llyexpressed

inangiogenicendo

thelia

Album

in-based

nano

conjugates

with


which

ares

mallhigh

lyspecificand

noncytotoxic

Tumor

spheroidso

fA375GFP

cell

tumor

spheroid

study

usingA375GFP

cells

toconfi

rmtheu

ptake

andpenetrationof

nano

conjugates

inthree-dimensio

nal

(3D)c

ulture

[128]


ble1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Paclitaxel

2-3


cid

(HA)CD

44

Paclitaxel-u

ltrasmallH

A(3ndash5

kDa)

nano

conjugates

internalized

viaC

D44

receptor-m

ediatedendo

cytosis

which

allowed

paclitaxelto

bypasstheP

-glycoprotein-

mediatedeffl

uxon

thes

urface

ofcancer

cells

Brainmetastasis

ofbreastcancer

using

MDA-

MB-231Br

breastcancer

cells

ivinjectio

n

[129]

Goldnano

particles

Chem

iresistorsbasedon

functio

nalized

gold

nano

particlesin

combinatio

nwith

patte

rnrecogn

ition

metho

ds

5mdash

Asensor

arrayforb

reathtesting

ofexhaledbreath

inlung

cancer

patie

nts

Ano

ninvasive

diagno

stictoolfor

lung

cancer

invitro

array

[137]

Goldnano

particles

magnetic

microparticles

AnassayforP

SAdetectionwith

gold

nano

particlesb

ased

onthe

PSA-

specificA

bsandshortD

NA

sequ

ences(barcod

es)

30Prostate-specific

antig

en(PSA

)

Magnetic

microparticles

conjug

ated

with

PSA-

specific

antib

odiestoextracttrace

amou

ntso

fthe

targetanalyte

(PSA

)inserum

samples

from

patie

ntsa

ndgold

nano

particles

with

PSA-

specifica

ntibod

iesa

ndshortD

NAsequ

ences(the

barcod

es)atta

ched

todetectthis

analyte

Anultrasensitive

assayforp

rosta

tecancer

invitro

barcod

earray

[138]

Carbon

nano

tube

Sing

le-w

alledcarbon

nano

tube

(SWCN

T)with

fluorescence

labelling

200ndash

300

mdashBiod

istrib

utionandexam

ination

ofglom

erular

filtrationin

kidn

ey

NIR

fluorescence

imagingdynamic

PETim

aging

invitro

(HK-

2cells

atthetranswell)

invivo

(mice

NCr

nunu

)ivinjectio

n

[147]

Water

solublec

arbo

nnano

tubes

functio

nalized

with

PEGradio

labels

andRG

Dpeptide

1ndash5(diameter)

100ndash

300(le

ngth)

RGDin

tegrins120572

]1205733

RGD-pegylated

SWCN

Ts

radio-labelledSW

CNTs

U87MGhu

man

glioblastomaa

ndHT-29

human

colorectalcancer

cell

linesU

87MGand

HT-29

tumou

rxeno

graft

mod

elsfor

biod

istrib

ution(PET

)ivinjectio

n

[148]

Graph

ene

Nanograph

enes

heet(N

GS)

for

phototherm

altherapy(PTT

)10ndash50

mdashSix-armed

PEG-N

GSwith

fluorescent

labelin

g

4T1b

earin

gBa

lbc

miceKB

andU87MG

xeno

graft

mod

els

PTT

ivinjectio

n

[155]


Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage


tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL


cidRG


(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Re

centlydevelopednano

platform

sfor

cancer

targetingin

preclin

icalstu

dies

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Lipo

somes

Doxorub

icin

108

CyclicA

sn-G

ly-Arg

(cNGR)

peptidesCD13

and

aminop

eptid

aseN

cNGRdecorated

lysolip

id-con

tainingtemperature

sensitive

liposom

es

Hum

anfib

rosarcom

a(H

T-1080)

invitro

bind

ingstu

dy[95]

Lipo

somes

inorganic

nano

particles

(goldnano

rods

irono

xide

nano

worms)

Doxorub

icin

55

Atrun

cated

tumor-ta

rgeted

human


RGD)toindu

cecoagulationon

bind

ingto


toheatspecifically

directed

coagulation-cascade

activ

ationin

tumou

rs


odules

(PEG

-decorated

gold

nano

rods

tumor-ta

rgeted

trun

catedtissue

factor

proteins)thattarget

tumorsa

ndthen

locally

activ

ate

thec

oagu

latio

ncascadeto

broadcasttum

orlocatio

nto


nano


carryad

iagn

ostic

ortherapeutic

cargo(iron

oxiden

anow

orms

doxorubicin-loaded

liposom

es)

Invivo

MDA-

MB-435

xeno

graft

tumors

ivinjectio

n[97]

Lipo

somes

carbon

nano

tubes

Paclitaxel

164

anti-ErBb

2(H

er2)

mAb

Each

nano

horn

encapsulated

with

inon

eimmun

oliposom

eform

ulated

with

PEGand

thermallysta

blea

ndpH

sensitive

phosph

olipidsfor

pHsensitive

andprolon

gedreleaseo

fpaclitaxel

SK-BR-3andBT

-20

breastcancer

cells

invitro

cytotoxicity

[98]

Polymericnano

particles

siRNA

80times320

mdash

Catio

niclipid-coatedPL

GA

nano

particlesau

niqu

esoft

litho

graphy

particlemolding


nonw

ettin

gtemplatesP

RINT)

Invitro

prostate

cancer

celllin

es[108]

Polymericmicelles

12-D

iaminocyclohexane-

platinum

(II)(D

ACHPt)(thep

arent

complex

ofoxaliplatin

)30

mdash

Long

-circ

ulatingdrug-lo

aded

polymericmicellese

nhancing

tumou

rpermeabilitywith

aTG

F120573inhibitor

Poorlyperm

eable

pancreatictumorsin

them

icem

odel(C

26or

BxPC

3tumors)

ivinjectio

n

[209]

Nanocon

jugates

Splice-sw

itching

oligon

ucleotides

(SSO

s)(pho

spho

rodiam

idate

morph

olinooligom

er(PMO))

13

RGDin

tegrin120572]1205733a

cell

surfa

ceglycop

rotein

thatis

preferentia

llyexpressed

inangiogenicendo

thelia

Album

in-based

nano

conjugates

with


which

ares

mallhigh

lyspecificand

noncytotoxic

Tumor

spheroidso

fA375GFP

cell

tumor

spheroid

study

usingA375GFP

cells

toconfi

rmtheu

ptake

andpenetrationof

nano

conjugates

inthree-dimensio

nal

(3D)c

ulture

[128]


ble1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Paclitaxel

2-3


cid

(HA)CD

44

Paclitaxel-u

ltrasmallH

A(3ndash5

kDa)

nano

conjugates

internalized

viaC

D44

receptor-m

ediatedendo

cytosis

which

allowed

paclitaxelto

bypasstheP

-glycoprotein-

mediatedeffl

uxon

thes

urface

ofcancer

cells

Brainmetastasis

ofbreastcancer

using

MDA-

MB-231Br

breastcancer

cells

ivinjectio

n

[129]

Goldnano

particles

Chem

iresistorsbasedon

functio

nalized

gold

nano

particlesin

combinatio

nwith

patte

rnrecogn

ition

metho

ds

5mdash

Asensor

arrayforb

reathtesting

ofexhaledbreath

inlung

cancer

patie

nts

Ano

ninvasive

diagno

stictoolfor

lung

cancer

invitro

array

[137]

Goldnano

particles

magnetic

microparticles

AnassayforP

SAdetectionwith

gold

nano

particlesb

ased

onthe

PSA-

specificA

bsandshortD

NA

sequ

ences(barcod

es)

30Prostate-specific

antig

en(PSA

)

Magnetic

microparticles

conjug

ated

with

PSA-

specific

antib

odiestoextracttrace

amou

ntso

fthe

targetanalyte

(PSA

)inserum

samples

from

patie

ntsa

ndgold

nano

particles

with

PSA-

specifica

ntibod

iesa

ndshortD

NAsequ

ences(the

barcod

es)atta

ched

todetectthis

analyte

Anultrasensitive

assayforp

rosta

tecancer

invitro

barcod

earray

[138]

Carbon

nano

tube

Sing

le-w

alledcarbon

nano

tube

(SWCN

T)with

fluorescence

labelling

200ndash

300

mdashBiod

istrib

utionandexam

ination

ofglom

erular

filtrationin

kidn

ey

NIR

fluorescence

imagingdynamic

PETim

aging

invitro

(HK-

2cells

atthetranswell)

invivo

(mice

NCr

nunu

)ivinjectio

n

[147]

Water

solublec

arbo

nnano

tubes

functio

nalized

with

PEGradio

labels

andRG

Dpeptide

1ndash5(diameter)

100ndash

300(le

ngth)

RGDin

tegrins120572

]1205733

RGD-pegylated

SWCN

Ts

radio-labelledSW

CNTs

U87MGhu

man

glioblastomaa

ndHT-29

human

colorectalcancer

cell

linesU

87MGand

HT-29

tumou

rxeno

graft

mod

elsfor

biod

istrib

ution(PET

)ivinjectio

n

[148]

Graph

ene

Nanograph

enes

heet(N

GS)

for

phototherm

altherapy(PTT

)10ndash50

mdashSix-armed

PEG-N

GSwith

fluorescent

labelin

g

4T1b

earin

gBa

lbc

miceKB

andU87MG

xeno

graft

mod

els

PTT

ivinjectio

n

[155]


Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage


tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL


cidRG


(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




ble1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Paclitaxel

2-3


cid

(HA)CD

44

Paclitaxel-u

ltrasmallH

A(3ndash5

kDa)

nano

conjugates

internalized

viaC

D44

receptor-m

ediatedendo

cytosis

which

allowed

paclitaxelto

bypasstheP

-glycoprotein-

mediatedeffl

uxon

thes

urface

ofcancer

cells

Brainmetastasis

ofbreastcancer

using

MDA-

MB-231Br

breastcancer

cells

ivinjectio

n

[129]

Goldnano

particles

Chem

iresistorsbasedon

functio

nalized

gold

nano

particlesin

combinatio

nwith

patte

rnrecogn

ition

metho

ds

5mdash

Asensor

arrayforb

reathtesting

ofexhaledbreath

inlung

cancer

patie

nts

Ano

ninvasive

diagno

stictoolfor

lung

cancer

invitro

array

[137]

Goldnano

particles

magnetic

microparticles

AnassayforP

SAdetectionwith

gold

nano

particlesb

ased

onthe

PSA-

specificA

bsandshortD

NA

sequ

ences(barcod

es)

30Prostate-specific

antig

en(PSA

)

Magnetic

microparticles

conjug

ated

with

PSA-

specific

antib

odiestoextracttrace

amou

ntso

fthe

targetanalyte

(PSA

)inserum

samples

from

patie

ntsa

ndgold

nano

particles

with

PSA-

specifica

ntibod

iesa

ndshortD

NAsequ

ences(the

barcod

es)atta

ched

todetectthis

analyte

Anultrasensitive

assayforp

rosta

tecancer

invitro

barcod

earray

[138]

Carbon

nano

tube

Sing

le-w

alledcarbon

nano

tube

(SWCN

T)with

fluorescence

labelling

200ndash

300

mdashBiod

istrib

utionandexam

ination

ofglom

erular

filtrationin

kidn

ey

NIR

fluorescence

imagingdynamic

PETim

aging

invitro

(HK-

2cells

atthetranswell)

invivo

(mice

NCr

nunu

)ivinjectio

n

[147]

Water

solublec

arbo

nnano

tubes

functio

nalized

with

PEGradio

labels

andRG

Dpeptide

1ndash5(diameter)

100ndash

300(le

ngth)

RGDin

tegrins120572

]1205733

RGD-pegylated

SWCN

Ts

radio-labelledSW

CNTs

U87MGhu

man

glioblastomaa

ndHT-29

human

colorectalcancer

cell

linesU

87MGand

HT-29

tumou

rxeno

graft

mod

elsfor

biod

istrib

ution(PET

)ivinjectio

n

[148]

Graph

ene

Nanograph

enes

heet(N

GS)

for

phototherm

altherapy(PTT

)10ndash50

mdashSix-armed

PEG-N

GSwith

fluorescent

labelin

g

4T1b

earin

gBa

lbc

miceKB

andU87MG

xeno

graft

mod

els

PTT

ivinjectio

n

[155]


Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage


tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL


cidRG


(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table1Con

tinued

Nanop

latfo

rms

Drug

Averages

ize(nm

)Ligand

target

Descriptio

nsPo

ssibleapplications

References

Redu

cedgraphene

oxide(RG

O)for

PTT

20ndash80

Hum

anm

urinec

himeric

IgG1m

Ab(TRC

105)both

human

andmurineC

D105

RGOconjugated

tothe

anti-CD

105antib

odyTR

C105

Tumor

vasculature

targetingandim

aging

inlivingmicea

satheranostic

agent

invitro

(4T1

murine

breastcancerM

CF-7

human

breastcancer

andhu

man

umbilical

vein

endo

thelialcells

(HUVEC

s))

invivo

(4T1

breast

cancer

mod

el)

ivinjectio

n

[156]

Phage


tk+

ganciclovir+

[18F]FD

Gand

[18F]FE

AU7times1000

RGD4C

integrins

Hybrid

vector

with

adeno-associated

virus(AAV

)andfd-te

tderived

bacterioph

age

[AAV

phage

(AAV

P)]

RGD-4CAAV

P-HSV

tk(herpes

simplex

virusthymidinek

inase)

KS1767

cells

RGD-4C

AAV

P-HSV

tkPE

Tim

ages

with

[18F]FD

Gand[18F]FE

AUob

tained

before

and

after

ganciclovir

treatment

[194]

Magnetic

ironoxide[(m

aghemite

(120574-Fe 2O

3)or

magnetite(Fe

3O4)]for

MRI

66times880

Acidicandric

hin

cyste

ine

(SPA

RC)

SPARC

-binding

peptide

(SPP

TGIN

)and

triglutamate

display

edon

p3andp8

coat

proteins

ofM13

phage

respectiv

ely

Tumor

targeting

againstp

rosta

tecancer

[202]

mAb

mon

oclonalantibod

yPE

Gpolyethyleneg

lycolPL


cidRG


(Arg-G

ly-Asp)


ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




ble2Nanom

edicines

inclinicaltria

ls

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Lipo

somes

Doxorub

icin

(Myocet)

PhaseIII

NT

mdash100ndash

230

NoIRRshighrespon

se

andredu

cedcardiotoxicity

Kapo

sirsquossarcomaa

ndmetastatic

breastcancer

(phase

III)

Vincris

tines

ulfate

(Marqibo

)

FDAapproved

(Ph-adultA

LL)

PhaseII(NHL)

PhaseI

(pediatric

ALL

)

NT

mdash115

Extend

edPK

Acutelym

phocytic

leuk

emia(A

LL)a

ndno

n-Hod

gkinrsquoslymph

oma

(NHL)

Cytarabine

Dauno

rubicin

(CPX

-351)

PhaseIII

NT

mdash100

Extend

edPK

high

respon

seAc

utem

yeloid

leuk

emia

(AML)

Paclitaxel

(End

oTAG

-1)

PhaseIII

NT

mdash160ndash

180

Catio

nicliposom

alform

ulation

Vario

ussolid

tumors

Lurtotecan

(OSI-211N

X211)

PhaseIIcom

pleted

NT

mdash150

Redu

cedmyelosupp

ression

andhigh

respon

seOvaria

ncancer

Paclitaxel

(LEP

-ETU

)Ph

aseIIcom

pleted

NT

mdash150

NoIRRs

andhigh

respon

seMetastatic

breastcancer

Camptothecin

(S-C

KD-602)

PhaseIII

NT

mdash100

Pegylatedlip

osom


edPK

Advanced

solid

tumors

Oxalip

latin

(MBP

-426)

PhaseIII

Ttransfe

rrintr

ansfe

rrin

receptor

180

Extend

edPK

Advancedm

etastatic

solid

tumors

Doxorub

icin

(MCC

-465)

PhaseI

(disc

ontin

ued)


fhum

anmAb

GAHor

tumor-specific

antig

en140

Nohand

-foot

synd

romeo

rcardiotoxicity

Metastatic

stomachcancer

p53gene

(SGT5

3-01)

PhaseIb

TscFvtr

ansfe

rrin

receptor

90Im

proved

respon

seSolid

tumors

RB94

plasmid

DNA

(SGT-94)

PhaseI

TscFvtr

ansfe

rrin

receptor

108

Improved

respon

seSolid

tumors

Doxorub

icin

(MM-302)

PhaseI

TscFvErbB2

(HER

2)75ndash110

Advanced

breastcancer

Melanom

aantigens

andIFN120574

(Lipovaxin-M

M)

PhaseI

TSing

ledo

mainantib

ody(dAb

)fragment(VH)DC-

SIGN

Stableandsafe

Melanom

avaccine

Polymers

Paclitaxel

(Genexol-PM)

Approved

(Korea)

phaseIII

II(U

SA)

NT

mdashlt50

Polymericmicelles


TD

high

respon

se

Metastatic

breastcancer


ma

Paclitaxel

(NK1

05)

PhaseIII

NT

mdash85

Core-shell-typep

olym

eric

micellesextend

edPK

high

respon

seand

redu

ced

hypersensitivity

Metastaticrecurrent

breast

cancer


Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

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ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

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peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

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Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table2Con

tinued

Nanop

latfo

rms

Drug

Currentstatus

Mod

eof

deliverylowast

Ligand

target

Averages

ize

(nm)

Descriptio

nsTy

peso

fcancer

Polymers

Doxorub

icin

(SP1049C

)Ph

aseI

completed

NT

mdash30

Polymericmicelles

high

respon

seand

nohand

-foot

synd

rome

Advanced

adenocarcino

ma

ofesop

hagusa

ndgastr

oesoph

agealsystem

Doxorub

icin

(NK9

11)

PhaseII(As

ia)

NT

mdash40

Polymericmicelles

extend

edPK

Metastatic

recurrent

solid

tumors

Paclitaxel-p

oliglumex

(Opaxio)

PhaseIII

NT

mdash10ndash150

Polymericmicelles

extend

edPK

Ovaria

ncancer

Camptho

tecin

(CRL

X101)

PhaseIbIIa

NT

mdash20ndash50

ApH

-sensitivep

olym

ernano

carrierrele

asing

camptothecinin

thea

cidic

environm

ento

fcancer

cellsextendedPK

and

high

respon

se

Advanced

solid

tumors

Irinotecan

(SN-38NK0

12)

PhaseIII

NT

mdash20


activ

emetaboliteso

fcamptothecinderiv

ative

andextend

edPK

Solid

tumors

Cisplatin

(NC-

6004

Nanop

latin

)Ph

aseIII

(Asia

)NT

mdash30

Polymericmicelles

and

extend

edPK

(with

thea

imof

redu

cing

kidn

eytoxicity

comparedwith

cisplatin

alon

e)

Advancedm

etastatic

pancreaticcancer

(evaluatingnano

platin

incombinatio

nwith

gemcitabine

inpatie

nts

with

advanced

ormetastatic

pancreatic

cancer)

Docetaxel

(BIN

D-014)

PhaseI

completed

T

PeptidePS

MA

(solid

ormetastatic

prostate

cancer

cells

bybind

ingto

prostate-specific

mem

brane

antig

en)

100

Enhanced

therapeutic

efficacy

andpartial

respon

seSolid

tumors

RRM2siR

NA

(CALA

A-01)

PhaseI

TTransfe

rrintr

ansfe

rrin

receptor

70

Cyclo

dextrin

-based

nano

particlecontaining

anti-RR

M2siR

NAandno

DLTs

Solid

tumors

PKpharm

acok

ineticsDRR

drugreleaser


reactio

nsP

h-P

hiladelphiaC

hrom

osom

eNegativeMTD

maxim

umtolerabled

oseDLTsdo

se-limiting

toxicitiesDC

dend

riticcell

lowastMod

eofd

eliveryNT

nontargeted(passiv

etargetin

g)T


g)


Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table3FD

Aapproved

antic

ancerd

rugs

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Lipo

somes

Abelcet

Enzon

Lipo

somalam

photericin

BFu

ngalinfections

iv

AmBisome

Gilead

Sciences

Lipo

somalam

photericin

BFu

ngalandprotozoal

infections

iv

Amph

otec

ThreeR

ivers

Pharmaceutic

als


amph

otericin

BFu

ngalinfections

iv

DepoC

ytSkyePh

arma

Lipo

somalcytarabine

Malignant

lymph

omatou

smeningitis

it

Dauno

Xome

Gilead

Sciences

Lipo

somaldaun

orub

icin

HIV-related

Kapo

sirsquos

sarcom

aiv

DoxilCa

elyx

Ortho

Biotech

Scherin

g-Plou

ghLipo

some-PE

Gdo

xorubicin

HIV-related

Kapo

sirsquos

sarcom

ametastatic

breastcancerand

metastatic

ovariancancer

im

Myocet

Zeneus

Lipo

somaldo

xorubicin

Com

binatio

ntherapywith

cyclo

phosph

amidein

metastatic

breastcancer

iv

Visudyne

QLTN

ovartis

Lipo

somalverteporfin

Photod

ynam

ictherapy

(PDT)

fora

ge-related

macular

degeneratio


ocular

histo

plasmosis

iv

Polymers

Adagen

Enzon

PEG-adeno

sined

eaminase

Severe

combined

immun

odeficiency

diseasea

ssociatedwith

ADAdeficiency

im

Cop

axon

eTE

VAPh

armaceutic

als


L-lysin

eandL-tyrosin

ecopo

lymer

Multip

lesclerosis

sc

Genexol-PM

Samyang

Metho

xy-PEG

-poly(D


Metastatic

breastcancer

iv

Macugen

OSI

Pharmaceutic

als

PEG-anti-V

EGFaptamer

Age-rela

tedmacular

degeneratio

nir


Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Table3Con

tinued

Nanop

latfo

rms

Drug

Com

pany

Prop

ertie

sIndicatio

nsRo

utes

ofadministratio

n

Neulasta

Amgen

PEG-G

CSF

Neutro

peniaa

ssociated

with

cancer

Chem

otherapy

sc

Oncaspar

Enzon

Pegaspargase

(PEG

-L-asparaginase)

Acutelym

phob

lastic

leuk

emia

ivim

Renagel

Genzyme

Poly(allylamine

hydrochloride)

End-stager

enaldisease

Oral

Somavert

NektarPfi

zer

PEG-H

GF

Acromegaly

sc

Others

Abraxane

AbraxisB

ioScience

AstraZ

eneca

Album

in-bou

ndpaclitaxel

Metastatic

breastcancer

iv

Estrasorb

Novavax

Estradiolemulsio

nVa

somotot

symptom

sassociated

with

menop

ause

Topicaland

transdermal

Emend

ElanM

erck

Nanocrystallin

eaprepitant

Antiemetic

Oral

MegaceE

S

Strativ

aPh

armaceutic

als

subsidiary

ofPar

Pharmaceutic

alInc

Nanocrystallin

emegestro

lacetate

Ano

rexiacachexiaora

nun

explainedsig

nificant

weightlossinAID

Spatie

nts

Oral

Rapamun

eElanW

yeth

Pharmaceutic

als

Nanocrystallin

esiro

limus

Immun

osup

pressant

Oral

TriCor

ElanA

bbott

Nanocrystallin

efenofi

brate

Antihyperlip

idem

icOral

Ferid

exBa

yerH

ealth

care

Pharmaceutic

als

Femmoxides

solutio

n(sup

erparamagnetic

iron

oxide)

MRI

contrastagent

iv

ADAa

deno

sinedeam

inase

GCS


ulatingfactorH

GF

hepatocyte

grow

thfactorH

IVh

uman

immun

odeficiency

virusim

intram


intravenou

sPE


subcutaneousV

EGFvascular

endo

thelialgrowth

factor


Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




Cancer cell

Cancer targeting



interaction


trafficking









2











































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










































6 Conclusion






Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







Acknowledgments


References































































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




































































































































































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



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