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Reviews�KEYNOTEREVIEW
Drug Discovery Today � Volume 00, Number 00 �December 2015 REVIEWS
Teaser The present review provides a novel platform to scientist for CNTsand their conjugation chemistry, interactions, conjugation, and their
potential biological applications in drug delivery perspectives.
Interactions between carbonnanotubes and bioactives: a drugdelivery perspectiveNeelesh Kumar Mehra and Srinath Palakurthi
Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy,
Texas A & M Health Science Centre, Kingsville, TX 78363, USA
Applications of carbon nanotubes (CNTs) in the biomedical arena have
gained increased attention over the past decade. Surface engineering of
CNTs by covalent and noncovalent modifications enables site-specific
drug delivery and targeting. CNTs are available as single-, double-, triple-,
and multiwalled carbon nanotubes (SWCNTs, DWCNTs, TWCNTs, and
MWCNTs, respectively) and have unique physicochemical properties,
including a high surface area, high loading efficiency, good
biocompatibility, low toxicity, ultra lightweight, rich surface chemistry,
non-immunogenicity, and photoluminescence. In this review, we
highlight current understanding of the different types of physical and
chemical interaction that occur between therapeutics and CNTs, and the
potential application of the latter in drug delivery and imaging. Such
understanding will aid exploration of the utility of multifunctional CNTs
as pharmaceutical nanocarriers, and potential safety and toxicity issues.
Multifunctional CNTs: a new contour in drug delivery and targetingCarbon nanomaterials, including carbon nanohorns (CNHs), graphenes (GRs), carbon nanorods
(CNRs), polyhydroxy fullerenes (PHF) and CNTs, represent safe and efficacious carrier systems for
drug delivery and drug targeting because of their unique physicochemical properties. CNTs were
first discovered by Roger Bacon in 1960, and were described fully by Sumio Iijima. CNTs are now
the focus of many studies exploring their applications in drug delivery and drug targeting, as well
as cosmetic products [1,2].
CNTs are ultra-light-weight, tubular, hollow monolithic structures, with a high surface:aspect
ratio (length/diameter), rich functional surface chemistry and high drug-loading capacity. They
are also biocompatible, nonimmunogenic, and photoluminescent, making them attractive
nanocarriers for drug delivery and imaging. CNTs do not require any type of fluorescent labeling
for detection because they can be detected directly because of their electron emission properties
[3–6]. CNTs are available as SWCNTs, DWCNTs, TWCNTs and MWCNTs, with cylindrical
graphitic layers [7–10].
Functionalization is a well-known approach for altering the surface of nanocarriers by
attaching a variety of different bioactives. Functionalized CNTs (f-CNTs) have been used to
Neelesh Kumar Mehra
Dr Mehra is a research
scientist in the Department of
Pharmaceutical Sciences, Irma
Lerma Rangel College of
Pharmacy, which is part of the
Texas A & M Health Science
Center. His research interests
lie in the field of drug delivery
and targeting for cancer theragnostics using carbon
nanomaterials, quantum dots, nanoparticles, and
dendrimers. Dr Mehra has (co)-authored more
than >40 publications in international journals and
has published six book chapters in the field of carbon-
based nanomaterials.
Srinath Palakurthi
Dr Palakurthi is a professor
and director of graduate
studies in the Department of
Pharmaceutical Sciences, Irma
Lerma Rangel College of
Pharmacy, which is part of the
Texas A & M Health Science
Center. He gained his PhD
from the Indian Institute of Chemical Technology. His
current research interests encompass novel polymers
for gene therapy, polymer-based nanoparticles for the
targeted delivery of chemotherapeutics for the
treatment of ovarian cancer, mucosal delivery
of chemotherapeutics and antigens, and cellular
trafficking of nanoconstructs. He has (co)-authored
various publications in international journals related
to his research interests
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon nanotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.11.011
Corresponding author: Palakurthi, S. (palakurthi@pharmacy.tamhsc.edu)
1359-6446/� 2015 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.drudis.2015.11.011 www.drugdiscoverytoday.com 1
DRUDIS-1717; No of Pages 13
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REVIEWS Drug Discovery Today � Volume 00, Number 00 �December 2015
deliver both lipophilic (paclitaxel and docetaxel) [11,12], and
hydrophilic drugs (doxorubicin hydrochloride; DOX) [13–16].
CNTs readily cross different biological barriers, passing through
the plasma membrane and entering the cytoplasm through a ‘tiny
nanoneedle’ mechanism, which facilitates the transport and de-
livery of the cargo molecules or therapeutics into the target tissue
[2,6,17].
Purification, dispersion, and oxidation of CNTsThe physicochemical properties of CNTs, such as surface topog-
raphy, solubility, hybridization state, mechanical properties, ther-
mal conductivity, and structural and metallic or carbonaceous
impurities, need to be determined before they can be used in
pharmaceutical and biomedical applications [2,10,18]. There are
several factors (e.g., metal content, oxidation time, and oxidizing
agents and temperature used) that affect the purification efficiency
and yield of CNTs. The need for a mixture of strong acids (oxidiz-
ing agents) and corrosive solutions results in safety issues and,
therefore, appropriate precautions, such as the use of acid-resistant
gloves and adequate shielding, must be taken during their pro-
duction. Strong acid treatment not only removes any metallic
impurities, but also cuts the nanotubes into shorter pieces, gener-
ating oxygen-containing functional groups, such carboxylic (–
COOH) and hydroxyl (–OH), around the sidewalls and tips of
the tubes, where the curvature of the tubes results in a higher
strain on nanotubes structure [18–20]. The effect of oxidation on
the structural integrity of nanotubes was studied following acidic
(nitric acid and a mixture of sulfuric acid and hydrogen peroxide)
and basic (ammonium hydroxide/hydrogen peroxide) oxidation
processes. The increase in the number of surface oxygens per
chemical treatment (oxidation) followed the order: hydrochloric
acid (HCl) < ammonium hydroxide (NH4OH)/hydrogen peroxide
(H2O2) < piranha (H2SO4:HNO3) < refluxed nitric acid (HNO3).
Oxidation of CNTs with HNO3 under extreme conditions increases
the formation of defective CNTS because of shortening of the
length of nanotube [18].
Recently, Chajara and co-workers developed a fast, microwave-
assisted, organic solvent-free method for the efficient primary
purification of nanotubes [21]. The method dissociates and dis-
perses nonnanotube carbon in an organic solvent, resulting in
CNTs of high purity in few minutes, and with low few defects [21].
Alternatively, strong acids have also used to oxidize CNTs for
improving their dispersibility and purification [22]. The five meth-
ods used for the dispersion of hydrophobic nanotubes are: (i)
dispersion, reaction; (ii) dissolution, dispersion, precipitation;
(iii) dispersion, dispersion, precipitation; (iv) melt, powder, mix-
ing; and (v) no fluid mixing (reviewed in [23]). Methods (iv) and (v)
do not use any solvents [23].
The use of surfactants, such as sodium dodecyl sulfate (SDS) and
sodium dodecyl benzene sulfonate (SDBS), as coating agents to
improve the dispersibility of CNTs results in better long-term
stability. As an alternative, chitosan (CHI; a natural cationic
polysaccharide biopolymer obtained from the deacetylation of
chitin) can also be grafted onto the nanotube surface because of
its nontoxic, biocompatible and biodegradable properties [24,25].
CHI is an attractive way to encapsulate CNTs through hydrogen
bonding; for example, it enhanced the stability and sustained
release in vitro of DOX (degradation of chitosan and diffusion
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through chitosan shell) from DOX-loaded CHI–folic acid conju-
gated CNTs (CHI-FA-CNTs) as a result of their hydrophilic and
cationic charges [24].
Horie and coworkers examined the cellular influences of chem-
ical or biological reagents, such as pluronic F-127 and F-68, 1,2-
dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, the pulmonary
surfactant preparation Surfactent1), bovine serum albumin (BSA),
and Tween 80 as dispersants of CNTs in an experiment with the
human lung carcinoma A-549 cell line [26]. The adsorbed disper-
sant on the surface of the nanotubes was shown to induce oxida-
tive stress in the cells [26]. The poly-L-lysine (PLL)–MWCNTs
aqueous solution after appropriate modification enhanced the
aqueous dispersibility. After sonication, the black MWCNT–PLL
aqueous solution was stable for up to 240 days at pH 5.0 (Fig. 1)
[27]. The dispersion of MWCNT–SDBS (453 nm) was better com-
pared with that of MWCNT–PLL (488 nm) and MWCNT–SDS
(758 nm); however, tangle and aggregates were seen in water with
unfunctionalized MWCNTs (899 nm). These results show clearly
that SDS, SDBS, and PLL improve the aqueous dispersibility of
MWCNTs, and that MWCNT–SDBS and MWCNT–PLL disperse
better than MWCNT–SDS. Galactosylated CHI-grafted oxidized
MWCNTs (O-CNTs-LCH-DOX) were synthesized for pH-depen-
dent sustained release and hepatic tumor targeting of DOX. The
particle sizes of O-CNTs, O-CNTs-LCH, and O-CNTs-LCH-DOX
were 176.1 � 2.4, 217.5 � 3.2, and 286.3 � 4.1, respectively, with
a polydispersity index (PDI) of 0.39 � 0.02, 0.35 � 0.06, and
0.31 � 0.01, respectively. A venous irritation study was performed
on New Zealand white rabbits after intravenous injection of O-
CNTs, O-CNTs-LCH, and O-CNTs-LCH-DOX in normal saline at a
5-mg/kg DOX dose for three consecutive days. The O-CNTs-LCH-
DOX formulation showed good biocompatibility, low toxicity,
higher cellular uptake, and higher antitumor activity, as well
decreased vascular irritation (Fig. 1), compared with O-CNTs, O-
CNTs-LCH, and free DOX in HepG2 cells [28].
The potential of biosurfactants to aid the effective dispersion of
nanotubes needs to be explored further to render the CNTs safer.
Only after obtaining a clear dispersion of CNTs using various
chemical functionalization strategies, will we begin to understand
the interactions of CNTs with therapeutics.
CNT interactions with theragnosticsCNTs can be considered as good adsorbents because of their ability
to interact with guest molecules via different mechanisms on their
surface. The adsorption of guest molecules into CNT bundles can
occur inside the tubes (internal sites), in the interstitial triangular
channels between the tubes, on the outer surface of the bundle
(external sites), or in the grooves (major and minor) formed at the
contacts between adjacent tubes. The influence of chemical mod-
ifications resulting from acid treatment, followed by triethylene-
tetraamine (TETA), has been studied at each stage of chemical
treatment using different analytical tools (Fig. 2) [22]. However,
unavoidable imperfections or vacancies, such as Stone–Wales
defects, pentagons, heptagons, and dopants, have a crucial role
in determining the adsorption properties of CNTs [29,30]. Apart
from these imperfections, five interactions (i.e., hydrogen bond-
ing, hydrophobic effects, covalent, electrostatic, and p–p stacking
interactions) could have a role in the attachment of biomolecules
[31]. In terms of the closed ends of CNTs, small molecules are easily
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
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(a) (b) (c)(i) (i)
(ii)
(i)
(ii)
(ii)
(iii)
(v)
(iv)
0.2 µm 0.2 µm
0.2 µm 0.2 µm
CNTs O-CNTs O-CNTs-LCH O-CNTs-LCH-DOX
Drug Discovery Today
FIGURE 1
(a) Transmission electron microscopy (TEM) images of carbon nanotubes (CNTs): (i), O-CNTs (ii) , O-CNTs-LCH (iii) and O-CNTs-LCH-doxorubicin (DOX) (iv), anddispersion (v). (b) Unfunctionalized and functionalized multiwalled carbon nanotube (MWCNT) solutions after 6 h (i) and 30 days (ii), from left to right; MWCNTs,
MWCNT-sodium dodecyl sulfate (SDS), MWCNT-sodium dodecyl benzene sulfonate (SDBS), and MWCNT- poly-L-lysine (PLL). (c) MWCNT-PLL aqueous solutions at
different pH values after 2 days (i) and 240 days (ii), from left to right; pH 3, 5, 7, 9, and 11.Source: Reproduced, with permission, from [28] (a) and [27] (c).
RamanLight
scattering
Electronmicroscope
Elementalanalysis
FTIRXRD
NMR
DSC
XPS
TGA
CNTs
Drug Discovery Today
FIGURE 2
Characterization techniques for carbon nanotubes (CNTs). Abbreviations: DSC,differential scanning calorimetry; NMR, nuclear magnetic resonance
spectroscopy; TGA, thermo gravimetric analysis; XPS, X-ray photoelectron
spectroscopy; XRD, X-ray diffraction.
Reviews�KEYNOTEREVIEW
adsorbed most preferentially onto the external grooves and outer
walls of the nanotubes. The host–guest interaction depends on the
size of the guest molecules and interaction energy [32,33]. A few
studies have reported that CNTs are able to adsorb some toxic
substances, such as fluorides [34], dioxins, lead, and alcohols,
which are carcinogenic by-products of many industrial processes
[34–36]. This pioneering work established a new field of applica-
tions for CNTs as cleaning filters for many industrial processes
with hazardous by-products. CNTs could also be used as good
adsorbents for the removal of dichlorobenzene from wastewater
over wide range of pH. For example, 30 mg of organic molecule are
adsorbed per gram of CNT [37]. The nonspecific adsorption of
proteins on CNTs [38] is an interesting phenomenon, but repre-
sents a relatively less controllable mode of protein–nanotube
interaction.
Ji et al. investigated MWCNTs as potential adsorbents for the
removal of two sulfonamide antibiotics (sulfapyridine and sulfa-
methoxazole) from aqueous solutions. Both sulfonamide antibio-
tics are strongly adsorbed on to MWCNTs surfaces via p–p electron
interactions [39]. Since the discovery of CNTs, researchers have
been continuously exploring the interactions of CNTs with bio-
molecules (proteins, carbohydrates, and nucleic acids) for the de-
velopment of carbon nanocomposites for biomedical applications.
Hydrophobic interactionsThe hydrophobic nature of CNTs is best described by the prefer-
ential adsorption of different hydrocarbons (benzene, hexane,
and cyclohexane) over alcohols and organic molecules. There
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are problems associated with most anticancer drugs, including
taxol derivatives [paclitaxel (PTX), docetaxel (DTX)] [12,40,41],
and amphotericin B (AmB) [42], DOX [43,44], 10-hydroxycamp-
tothecin (HCPT) [45], etoposide (ETO) [46] and others, such as
small interfering (si)RNA [47], during formulation development,
but these can be ameliorated by conjugation through cleavable
disulfide bonds, hydrazone bonds with CNTs, and other nanos-
tructures [12,31].
p–p Stacking interactionCNTs can interact with organic molecules via p–p stacking inter-
actions. DOX interacts with the surface of CNTs to form supramo-
lecular complexes based on p–p stacking interactions, because
both have many p electrons [44,48]. Approximately 50–60%
(w/w) of DOX molecules can be attached to the surface of CNTs
via p–p stacking interactions. DOX molecules can also bind with
surface-modified CNTs noncovalently via hydrophobic and p–p
stacking interactions. The aromatic nature and relatively low
aqueous solubility of deprotonated DOX at basic pH conditions
can help it bind with nanotubes. Other aromatic molecules could
also be easily bound or wrapped with the backbone of the CNT and
released at the target site [44].
The p–p bonding interaction between organic molecules and
the surface of CNTs has been characterized by spectroscopy using
Raman, nuclear magnetic resonance (NMR), and fluorescence
techniques. Additionally, the p–p stacking interaction is affected
by the relative position of the benzene ring of organic molecules to
the hexagons present at the surface of the CNT. The p–p stacking
interaction is a noncovalent functionalization and allows con-
trolled release of the adsorbed drugs. Such a controlled release
approach has a significant impact on the development of nano-
pharmaceutical products in the treatment of cancer, HIV/AIDS,
and other diseases [24,31].
Linear poly (m-phenylenevinylene-co-2,5-dioctoxy-p-phenyle-
nevinylene) (PmPV) could wrap around CNTs or nanotube bun-
dles regardless of their diameter. Dendrimer–CNT electron donor–
acceptor monohybrids were also characterized after illumination
or by using different spectroscopic techniques. Several recently
published studies show that p–p interactions bind and wrap the
active theragnostics onto the engineered CNTs [6,13,24,34,41,
43,49–52].
Hydrogen-bonding interactionsHydrogen-bonding interactions also have a vital role in the
adsorption of numerous organic molecules and other chemicals
onto the surface of CNTs if functional groups, such as carboxylic
(–COOH), hydroxyl (–OH), amine (–NH2), and others, are present.
Surface-engineered CNTs can act as hydrogen-bonding acceptors
because of their aromatic nature, whereas carboxylic, hydroxyl,
phenolic, and amine groups act as hydrogen-bonding donors.
Therefore, surface-engineered nanotubes could bind with organic
chemical moieties via hydrogen-bonding interactions [12,31,44].
Covalent-bonding interactionsCovalent bonding can occur between organic reagents and active
functional groups containing nanotubes and are best illustrated
by different spectroscopic techniques, such as Fourier transform
infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy
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(XPS), small angle X-rays spectroscopy (SAXS), Raman spectrosco-
py, and NMR [3,51]. Covalent-bonding affinity to nanotubes is
higher compared with noncovalent-bonding interactions, which
can resist any desorption. Functionalization of CNTs can be
achieved with covalent modification via carboxylation [18], fluori-
nation, amidation, thiolation, and esterification [2]. Bioactive
molecules could be bound covalently to nanotubes via amide,
disulfide, ester, and carbamate bonds [2,31].
Electrostatic interactionsElectrostatic interactions are mainly related to the surface charge
potential of organic chemicals and CNTs. Electrostatic interac-
tions mainly occur when two oppositely charged molecules inter-
act, whereas electrostatic repulsion occurs between molecules
with the same charge. The pH-dependent adsorption of positively
charged (cationic) fluoroquinolone antibacterial agent (norfloxa-
cin) on CNTs was attributed to electrostatic interactions. Polyeth-
ylene imine (PEI), a cationic polyelectrolyte, was used to modify
acid-purified MWCNTs via electrostatic interactions between neg-
atively charged CNTs and PEI, and the physisorption process was
analogous to polymer wrapping [31,53].
Bioactives loading into surface-tailored CNTsPhysical loading of bioactivesSurface-engineered CNTs have unique properties facilitating their
role as nanocontainers wherein guest molecules could be filled
through the host–guest interaction mechanism depending upon
the diameter of the nanotube. Geometrical parameters have an
important role in determining the efficiency of host–guest mole-
cules interactions (i.e., the ratio of the internal diameter of the
nanotube to the size of the encapsulated molecule). The guest
molecule is unable to enter the nanotube if the diameter of the
latter is too small. If the diameter is too big, the host–guest
interaction might not be strong enough for the guest molecules
to be retained inside the nanotube. The most efficient host–guest
interaction mechanism is achieved when the van der Waals diam-
eter of the guest molecules matches the internal diameter of the
nanotubes. CNTs have an approximately 1.3-nm internal diameter
and fullerene C60 molecules, whose van der Waals diameter is
1.0 nm (an ideal geometric match), are referred to as having a
‘snug fit’. A snug fit ensures strong interactions between the guest
molecules and the sidewalls of the nanotubes in controlling the
chemical reactions of the encapsulated molecules as well as the
physicochemical properties of the nanotube itself [54].
From a chemist’s point of view, the most captivating property of
CNTs is their ability to load guest molecules inside their inner
cavity to achieve high loading efficiency, which is known as
‘endohedral filling’. Recently, researchers explored endohedral
filling via various interaction mechanisms. It is well known that
CNTs have many highly delocalized p electron structures, which
can be easily modified via p electron-containing moieties forming
p–p interactions [44].
The dual targeting of DOX to U87 human glioblastoma cancer
cells using folate-decorated magnetic MWCNTs has been reported
[24]. The DOX molecules became attached via p–p stacking and
hydrogen bonding, with a 96% loading efficiency when 0.5-mg FA-
MN-MWCNTs were loaded with <1 mg DOX (DOX:MWCNT < 2),
but decreased slightly to 92% with 1 mg DOX (DOX:MWCNT = 2).
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
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These novel folate-decorated MWCNTs showed enhanced cytotox-
icity toward U87 and human glioblastoma cells compared with
free DOX [52]. Similarly, a new family of folate-chitosan-decorated
SWCNTs showed the DOX-loading efficiency to be approximately
76% (plain SWCNTs) and approximately 91% (CHI-FA-SWCNTs)
via noncovalent p–p stacking interactions [24].
Cisplatin [cis-diaminedichloroplatinum (II, CDDP)], a US Food
and Drug Administration (FDA)-approved highly potent chemo-
therapeutic agent, was encapsulated into MWCNTs with a diame-
ter of approximately 13 nm via nano-extraction, resulting in a
final product that contained 21% CDDP [55]. In another report,
CDDP was encapsulated into MWCNTs based on the same princi-
ple of nano-extraction using ethyl acetate (EA) as an encapsulation
medium and capped with 1-octadecanethiol (ODT)-functionalized
gold nanoparticles (ODT-f-GNP), which constituted the ‘CNT
bottle’. The CNT bottle exhibited a higher amount of CDDP
loading (62.1%) over a shorter period of time (40 h) compared
with the previously published reports. The IC50 values of CDDP,
uncapped MWCNT-CDDP, and capped MWCNT-CDDP were
11.74, 12.92, and 7.74 MM, respectively [56]. Guven et al. evalu-
ated the anticancer activity of pluronic-F108 surfactant-wrapped
CDDP-encapsulated ultrashort SWCNTs (US-tube) against MCF-7
and MDA-MB-231 breast cancer cell lines. Cytotoxicities were
found to occur in both a dose- and time-dependent manner in
both the cell lines [57].
Loading of DOX into hybrid polyethylene-b-(polyethylene gly-
col) (PE-b-PEG)-CNTs at various pHs has also been reported [58].
The DOX-loading efficiency of these nanostructured hybrid car-
riers was 98% at pH 7.4, and approximately 42% and 61% at pH 2
and 10, respectively.
Based on these studies, we can conclude that surface-engineered
nanotubes have higher loading efficiency (up to 98%), which
could be exploited further in controlled and/or targeted drug
delivery. For example, thiol-modified siRNA cargo molecules were
linked to the amine functional groups on the sidewalls of phos-
pholipid–polyethylene glycol–SWCNTs (PL–PEG–SWCNTs) via
cleavable disulfide bonds. These disulfide linkages facilitate the
release of the cargo molecules from the SWCNT conjugate upon
cellular uptake [47].
Chemical conjugation of bioactivesOver the past two decades, several reports have been published
on drug–CNT conjugation and their application in drug delivery
and targeting. Covalent conjugation of a biomolecule (anticancer,
antifungal, antimalarial, and siRNA moieties) to the surface of
CNTs has been used to achieve the controlled release of the
conjugates either through hydrolytic cleavage and/or cleavable
disulfide bond linkages in a spatial and temporal release pattern. In
chemical conjugation, drug moieties with their chemical struc-
tures allow for conjugation while maintaining their inherent
geometry and hybridization in formulations. The conjugation
chemistry of nanotubes could provide new and exciting opportu-
nities in targeted and controlled drug delivery via cleavable bonds.
Chemical conjugation of AmB to the amino groups of engi-
neered CNTs using hydroxybenzotriazole (HOBT) and carbodii-
mide while preserving its high antifungal activity, was reported
in 2005 [42]. Benincasa and coworkers also synthesized two
conjugates with CNTs (SWCNTs and MWCNTs) with AmB to form
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f-CNT-AMB-1 and f-CNT-AMB-2 conjugates and tested them
against different strains of bacteria. f-CNTs-AMB-1 showed mini-
mum inhibitory concentration (MIC) values <10 mg/ml and dis-
played broad-spectrum activity against microorganisms (except
Candida famata SA550 strain, 20 g/ml). Moreover, f-CNTs 1 and
f-CNT 2 (without AmB) did not show any antifungal activity (MIC
80 g/ml) [59].
Dhar and coworkers conjugated platinum (IV) onto the surface
of SWCNTs. Initially, SWCNTs were sonicated with platinum (IV)-
PEG-NH2 for 1 h followed by centrifugation at 2.4 � 104 g for 16 h
to remove catalysts, whereas the large aggregates and free plati-
num (IV)-PEG-NH2 were removed by ultrafiltration. The platinum
(IV) complex (compound 1) and cisplatin [cis-dichlorodiammine-
platinum (II) or cis-DDP] were used as the controls in a cytotoxicity
study using the human nasopharyngeal epidermoid carcinoma
(KB), choriocarcinoma (JAR), and human testicular cancer (NTera-
2) cell lines. IC50 values of SWCNT-tethered 1 were 0.019 and 0.01
MM in FR(+) JAR and KB cells, respectively, whereas the IC50 values
of cis-DDP and compound 1 were 0.086 and 0.15 MM, respectively,
in KB cells. However, the IC50 value of SWCNT-1 increased to
0.0448 MM in folate receptor (FR–) NTera-2 cells, which demon-
strated targeted uptake through (FR+) cells. The platinum (IV)
attached PEG-NH2-SWCNTs improved cellular uptake of the drug
and achieved higher cell death rates [60].
HCPT was covalently attached to the outer surface of the
engineered MWCNTs via biocleavable ester bonds in the presence
of N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC) as coupling agents [45]. In another
study, both methotrexate (MTX) (an anticancer agent) and fluo-
rescein isothiocyanate (FITC; an imaging agent) were attached on
to the sidewall of MWCNTs via the 1,3 dipolar cylcoaddition
reaction of azomethineylide and were shown to be internalized
by human Jurkat cells [61]. Gonadotrophin-releasing hormone
(GnRH), which is overexpressed in the plasma membrane of
several types of cancer cell, was covalently anchored onto the
surface of the oxidized MWCNTs via an amide linkage [62].
The covalent immobilization of an anticancer drug (DOX) onto
the surface of functionalized SWCNTs via hydrazone linkage
formed by the condensation of the C-13 ketone of DOX with a
hydrazine was reported by Gu and coworkers [63]. The DOX was
conjugated on to PEGylated SWCNT through hydrazone bonds.
Amine groups of PEGylated SWCNT were first coupled with the
COOH– terminal functional groups of hydrazinobenzoic acid
(HBA) to form hydrazine-modified SWCNT using EDC and NHS
as catalysts. Thereafter, DOX was conjugated to the SWNTs via
acid-sensitive hydrazone bonds (SWNT-HBA-DOX) between the
hydrazine moiety attached to the SWNTs and the ketone group
of DOX.
A few studies have reported paclitaxel (PTX) conjugation to
both types of CNT via cleavable ester bonds to form stable and
aqueous soluble conjugates. PTX was conjugated to the carboxyl
functional groups of poly citric acid (a highly functional polymer
with a large number of carboxylic groups) via cleavable ester bonds
to obtain MWCNT-grafted-PCA-PTX conjugates with a drug con-
tent of 38% w/w [12]. Similarly, Liu et al. also conjugated PTX at
the 20-OH position to the terminal amine group of branched
DSPE-PEG5000-4-arm-(PEG-amine) on SWCNTs via cleavable ester
bonds, which showed higher efficacy in suppressing tumor growth
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
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REVIEWS Drug Discovery Today � Volume 00, Number 00 �December 2015
DRUDIS-1717; No of Pages 13
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EYNOTEREVIEW
compared with free PTX. These results suggest that higher con-
centrations of PTX were delivered to breast cancer cells using
SWCNT-PTX conjugates compared with using PTX alone [40].
Another taxol derivative, DTX was also conjugated with SWCNT
via p–p interactions, and further functionalized by the surfactant
polyvinylpyrrolidone K-30 (PVPk 30) and 1,2-distearoyl-sn-glycero-
3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]
(DSPEPEG 2000)-maleimide (DPM). The maleimide group at the
end of DPM covalently reacted with the cysteine in
CNGRRCK2HK3HK11 (C-containing sulfhydryl groups) [64].
Similarly, Chen et al. reported a novel strategy for engineering
functionalized SWCNTs. siRNA were bound to the amino func-
tional groups of the DSPE-PEG-amine via disulfide bonds to
achieve siRNA-mediated gene silencing in breast cancer cells [65].
PEGylation chemistry of CNTsPEG is a linear, uncharged, flexible organic molecule that is the most
widely used biocompatible polymer because of its nontoxicity,
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon ndx.doi.org/10.1016/j.drudis.2015.11.011
Tumor
NearIR
Tumorxenograft
Intratumoral injection(PEG-SWNTs or PBS) NIR irradiation
PBS
SWNT
Tumor growthDeath
Tumor destructionSurvival
O
O
OO
O
O OO
CN
H
P
SerumIn serum In P83
500 nm
2
1
2
6
(a)(f)
(g)
(h)
(b)
(e)
(c) (d)
FIGURE 3
Photothermal treatments for in vivo tumor ablation using polyethylene glycol (PE
procedure and results of PEG-SWCNT-mediated photothermal treatment of tumors
(KB) cells (70 mm3); (c) mouse after intratumoral injection of a PEG-SWCNT solution
3 min to tumor region showing the aqueous solution of PEG-SWCNTs. (e) Chemical schains of phospholipid-PEG on the sidewall of SWCNTs. (Inset) Photographs of fet
phosphate buffer saline (PBS, right). Atomic force microscope (AFM) image of indiv
SWCNTs for tumor obliteration. (f) Representative photographs of mice treated in
SWCNTs + NIR; II, untreated; III, PBS + NIR; IV, PEG-SWCNTs). (g) Four mice after 60dependent tumor growth curves of KB tumor cell xenografts.
Source: Reproduced, with permission, from Ref. [70].
6 www.drugdiscoverytoday.com
nonimmunogenicity, and excellent solubility in aqueous and or-
ganic solutions. PEG is approved by the FDA as a base for use in
pharmaceutical formulations. Conjugation of PEG to nanobioma-
terials (‘PEGylation’) has been a useful tool for certain carriers to
resist opsonization, and improve biocompatibility and solubility to
attain long blood circulation time in vivo. PEGylated nanotubes are a
novel class of targeted delivery system, capable pf efficiently deliv-
ering higher drug payloads to disease sites, for the treatment of
diseases such as cancer, TB, and leishmaniasis. PEGylation makes
the nanotubes hydrophilic and enhances their loading efficiency; it
also reduces their immunogenicity, antigenicity, and toxicity. The
PEGylation approach, depending upon the molecular weight (MW)
and surface density of the PEG chain, can overcome the problems of
first-generation nanotubes, such as their pulmonary and hemolytic
toxicities, and can also improve the stability kinetics, which is vital
for extended drug delivery [66]. PEGylation prevents nonspecific
phagocytosis by the reticuloendothelial systems (RES) [67,68]. For
a detailed review of the PEGylation of nanotubes, see [1].
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
Day
4 Day
0 Day
0 Day
I PEG-SWNTs + NIR II Untreated III PBS + NIR IV PEG-SWNTs
I PEG-SWNTs + NIR
3500
3000
2500
2000
1500
1000
500
0
0 5 10 15 20 25 30
Days
Mea
n t
um
or
volu
me
(mm
3 ) UntreatedPEG-SWNTsPBS + NIRPEG-SWNTs + NIR
Drug Discovery Today
G)-single-walled carbon nanotubes (SWCNTs). (a) Schematic view of the
in mice; (b) a mouse bearing human nasopharyngeal epidermoid carcinoma
(120 mg/l, 100 ml); (d) near-infrared (NIR) irradiation (808 nm, 76 W/cm3) for
tructure of PEG-SWCNTs, showing the strong adsorption of hydrophobic alkylal bovine serum (FBS, left), PEG-SWCNTs in fetal bovine serum (middle) and
idual PEG-SWCNTs deposited on a SiO2. In vivo photothermal effects of PEG-
different groups at various time points after each treatment (I, PEG-
days of photothermal treatment (I) from four independent sets. (h) Time-
Drug Discovery Today � Volume 00, Number 00 �December 2015 REVIEWS
DRUDIS-1717; No of Pages 13
Reviews�KEYNOTEREVIEW
The intracellular distribution of FITC-labeled PEGylated
SWCNTs (FITC-PEG-SWCNTs) in living cells was investigated by
Cheng and coworkers [69]. FITC-PEG-SWCNTs entered the nucle-
us via energy-dependent processes. The FITC-PEG-SWCNTs did
not cause any discernible changes in the nuclear organization and
had no effect on the growth kinetics and cell cycle distribution up
to 5 days post-administration. Thus, the intracellular PEGylated
SWCNTs were highly dynamic and their cell penetration capacity
was found to be bidirectional [69].
Additionally, CNTs have photon-to-thermal abilities and are a
useful candidate for photothermal therapy because they generate
significant amount of heat by excitation of near-infrared light
(NIR). In vivo NIR-mediated tumor destruction by photothermal
effects using PEGylated SWCNTs was studied by Moon and co-
workers [70], who found that the PEGylated SWCNTs destroyed
solid malignant tumors completely in mice in a non-invasive
manner without any adverse effects (Fig. 3) [70].
Biodistribution and blood clearance of PEGylated SWCNTs as
drug delivery vehicles for cisplatin in mice has also been reported
[71]. Cheng and coworkers investigated the use of PEGylated CNTs
in multidrug resistant (MDR) cancer chemotherapy [72]. Based on
atomic force microscopy (AFM) examination, the authors found
the mean length of the PEGylated CNTs to be approximately
0.9 � 0.7 mm, with a median length of 0.55 mm, and an average
diameter of approximately 15 � 5.8 nm, and a median diameter of
14.5 nm. The PEGYlated CNTs were found to be efficient carriers
during chemotherapy treatment of MDR cancer [72].
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon ndx.doi.org/10.1016/j.drudis.2015.11.011
Dendrimers Micelles Nucleic acids Ang
Niosomes
Quantum dots
Carbon nanohorns
Liposomes Nanoparticles Proteins
FIGURE 4
Conjugation of carbon nanotubes (CNTs) using chemical and biological moieties, t
Abbreviation: HCPT, 10-hydroxycamptothecin.
A novel and simple ultraviolet-initiated ‘graft from’ polymeri-
zation method was introduced by Zhang and Henthor [73] to
synthesize PEGylated CNTs with significantly enhanced aqueous
dispersibility and long-term stability. Nie et al. functionalized
DWCNTs with two kinds of PEG azide (diazido-terminated PEG
and azido-terminated monomethylether; PEG800–DWNTs and
CH3O-PEG750–DWNTs, respectively) using [2 + 1] cylcoaddition,
which formed a highly stable suspension with good aqueous
solubility (0.36 and 0.37 mg/ml, respectively) [74]. PEG-grafted-
SWCNTs (PEG-g-SWCNTs) or PEG-grafted MWCNTs (PEG-g-
MWCNTs) was also synthesized by Lay and coworkers. PTX was
physically loaded onto CNTS, and the loading capacity (LD %) was
found to be 26% and 36% (w/w) for PEG-g-SWCNTs and PEG-g-
MWCNTs, respectively. However, PEGylated nanotubes reduced
the aggregation or agglomeration of nanotube and were nontoxic
in a mouse model [75]. Similarly, phospholipid-PEG-functional-
ized SWCNTs (PL-PEGs-SWCNTs) was synthesized by Hadidi et al.
using two types of PEG derivative (PL-PEG 2000 and PL-PEG 5000)
to improve their solubility in aqueous solution. Techniques, such
as D-optimal design and second-order polynomial equations, were
applied to investigate the effect of variables on PEGylation and the
solubility of SWCNTs. Optimization was performed for aqueous
solubility (found to be 0.84 mg/ml) and loading efficiency (nearly
98%) for PL-PEG 5000-SWCNTs conjugates and showed that the
increase in aqueous solubility is an essential criterion in the design
of a CNT-based drug delivery system. After the successful synthesis
of water-soluble nanotube conjugates, the authors evaluated the
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
iopep Antibodies Aptamers
GliotoxinCarboplatin
HCPT
Carbon nanotubes Oxaliplatin
Doxorubicin
Amphotericin B
O
OO
O
Pt
N
N
O
ON
N
OHS S
Drug Discovery Today
argeting ligands, nanocarriers, proteins, antibodies, nucleic acids, and drugs.
www.drugdiscoverytoday.com 7
REVIEWS Drug Discovery Today � Volume 00, Number 00 �December 2015
DRUDIS-1717; No of Pages 13
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effect of PEGylated nanotubes on the viability and proliferation of
cultured Jurkat cells. They concluded that the PEGylated SWCNTs
were substantially less toxic compared with SWCNTs and also
that the MW of PL-PEG had a role at higher concentrations, with
improved biocompatibility [76,77].
Angiopep-2 was successfully conjugated onto modified PEGy-
lated-oxidized MWCNTs (O-MWCNTs-PEG-ANG) for coopera-
tive dual-targeting to brain glioma using intracellular tracking
in vitro and fluorescence imaging in vivo [78]. Recently, Wu and
coworkers developed PEGylated MWCNTs as a sustained-release
drug delivery system using oxaliplatin (a third-generation plati-
num analog of 1,2-diaminocyclohexane). The loading of oxali-
platin into MWCNTs-PEG was found to be approximately 43.6%,
and only 34% of oxaliplatin was released into PBS medium
within 6 h. The authors claimed that the PEG-MWCNTs showed
a sustained release pattern with improved cytotoxicity of oxali-
platin on HT-29 cells [79]. The various chemical and biological
moieties, targeting ligands, nanocarriers, proteins, antibodies,
nucleic acids, and drug conjugations with functionalized CNTs
are shown in Fig. 4. Mehra and Jain recently discussed multi-
functional hybrid-CNTs with carbon nanohorns (CNHs), lipo-
somes, dendrimers, and nanoparticles in drug delivery and
targeting [4].
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon ndx.doi.org/10.1016/j.drudis.2015.11.011
COOH
COOH
EDC
CONH
CONH
FI
PEI
PEI
PEI
pH = 7.4pH = 5.8
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
00
0 10 20 30 40 50 60 70TIme (h)
(a)
(b) (c)
(d) (e)
0.5 1
Concentration (mg/L)DOX concentration ( µM)
2 4
DO
X r
elea
se (
%)
Cel
l via
blit
y (%
)
Cel
l via
bili
ty (
%)
0 1.25 2.5 5 10
PBS+HeL
MWCNT/
-FI-HA/DO
+HeLa
PBS+192
MWCNT/
-FI-HA/D
+1929
FIGURE 5
(a) Synthesis of multifunctional MWCNTs. (b) Release profile of DOX from MWCNConfocal microscopic images of HeLa and L929 cells treated with MWCNT/PEI-FI-HA
(d) free DOX and MWCNT/PEI-FI-HA/DOX complexes at DOX concentrations of 0–
concentrations of the complexes of between 1.25 and 10 mg/l.
Source: Reproduced, with permission, from Ref. [86].
8 www.drugdiscoverytoday.com
pH-responsive CNTsThe development of safe and effective nanomedicines by conju-
gating appropriate targeting ligands at the surface of engineered
CNTs is essential for binding to specific receptors that are over-
expressed at the desired target sites. Stimuli-responsive engineered
CNTs might offer interesting opportunities in targeted therapy
and could release bioactives in response to a specific stimulus, such
as light, temperature, and, most importantly, pH. Average extra-
cellular pH values at cancerous sites are 6.8. Such a low extracellu-
lar pH value is caused by hypoxia followed by the production of
lactate and protons in extracellular microenvironments, which
regulates glycolysis. The variation in pH values at cancer tissues
suggests new strategies to develop pH-sensitive targeted drug
delivery systems, such as pH-sensitive liposomes, nanoparticles,
and dendrimers, which could release bioactives at the endosomal
pH with minimum adverse effects and significantly enhance the
therapeutic efficacy of those bioactives [80].
The pH gradient has a pivotal role in the internalization of
nanocarriers via endocytosis and transport in endosomes and
lysosomes. Lysosomes (pH 4.5–5.0) and hydrolytic enzyme pH
is involved in the cleavage and/or degradation of biomolecules
in the cytosol. There are three factors that determine pH-respon-
sive drug release in the lysosomal pH microenvironment: (i)
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
CONH CONH
CONHCONH
FIFI
FIFI
EDC
HA-COOH
NHCO-HA
NHCO-HA
PEI
PEI
PEI
PEI
a
PEI
X
9
PEI
OX
MergedDOXFIBright fieldHocchst33342
Drug Discovery Today
T/PEI-FI-HA/DOX complexes (1 mg/ml) under different pH conditions. (c)/DOX complexes ([DOX] = 2 MM) for 2 h. MTT assay of HeLa cells treated with
4 MM for 24 h. (e) DOX-free MWCNT/PEI-FI-HA at corresponding DOX
Drug Discovery Today � Volume 00, Number 00 �December 2015 REVIEWS
DRUDIS-1717; No of Pages 13
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon nanotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://dx.doi.org/10.1016/j.drudis.2015.11.011
TABLE 1
Summary of the use of multifunctional CNTs after decoration with targeting, imaging, and biofunctional chemical moieties asnanomedicines for cancer treatment.
Conjugate
moieties/ligand
Receptors Chemotherapeutic
agent
Cell lines used In vivo model Outcomes Refs.
SWCNT
Angiopep-2 LDL receptor DOX BCEC and C6 cells Male Balb/C
mice
Median survival time of saline group, O-
MWNTs-PEG-ANG group, DOX group,
DOX-O-MWNTs-PEG group, and DOX-O-MWNTs-PEG-ANG group was 30, 33.5,
33.5, 36, and 43 days, respectively
[78]
Aptamer – – Molt-4 ad U266 cells Not performed Treatment of U266 cells with Dau-
aptamer-SWNT complex significantlyincreased viability to 78%, but did not
change viability of Molt-4 cells
[93]
Epidermal growthfactor (EGF)
EGF receptor Etoposide A-549 lung epithelialcancer cells
Not performed Cell death induced by EGF/CHI/SWCNTs-COOHs/ETO was 2.7 times
higher than due to ETO alone;
modified- and f-SWCNTs had only slight
cytotoxicity
[46]
SN-38 HCT 116 and HT 29 Not performed SN38 covalent conjugates with
SWCNTs25/py38 were cleave
enzymatically (carboxylesterase) and
showed controlled release with goodbiocompatibility
[94]
Folic acid Folate receptor DOX HCC SMMC-7721
cells
Female nude
Balb/C mice
DOX/FA/CHI/SWNTs shown negligible
toxicity to kidney and liver based on
histological examination; DOX/FA/CHI/SWNTs depressed growth of liver
cancer in nude mice compared with
free DOX
[13]
HER2 IgY HER-2 Not used MCF-7 and
SK-BR-3 cells
Not performed HER2 IgY-SWCNTs complex specifically
targeted HER2-expressing SK-BR-3 cells
but not receptor-negative MCF-7 cells
[89]
HA Hyaluronatereceptor
Salinomycin (SAL) CD 44++ Not performed SAL-SWNTs-CHI-HA selectivelyeliminated cancer stem cells (CSCs) in
AGS gastric cancer cells and inhibited
malignant behavior of gastric CSCs
[91]
NGR peptide CD 13 receptor 2-Methoxyestradiol MCF-7 cancercells
S180 tumorfemale Balb/C
mice
Inhibition ratio of NGR-SWCNTs-2MEwas approximately 88.2% at a
10.15 mg/ml dose after 72 h
[90]
Poly citricacid (PCA)
– PTX A-549 andSKOV3 cells
Not performed Cytotoxicity of MWNT-g-PCAPTX was13.3% higher at 5 nM concentration
compared with free PTX in SKOV3 cells
[12]
RGD Integrin avb3
receptor
DOX MCF-7 and
U87 cells
Not performed IC50 value for PL-SWCNTS-DOX (8 MM)
was higher than for free DOX (2 MM)
[44]
MWCNTDexamethasone
mesylate
Nuclear
receptor
DOX A-549 cells Not performed In vitro release of DOX was found
sustained release from the DOX/DEX-
MWCNTs at pH 5.5 with less hemolytic
[50]
Diameter
functionalized
– Platinum (IV) HeLa ad RAW
264.7cnells
Not performed Both Pt(IV)@CNT constructs were
poorly cytotoxic on macrophages and
induced negligible cell activation and
no proinflammatory cytokineproduction
[96]
Folic acid Folate
receptors
DOX MCF-7 cells Sprague-Dawley rats Median survival time of DOX/FA-PEG-
MWCNTs (30 days) compared with free
DOX
[92]
DTX MCF-7 cells Balb/C mice Tumor volume (mm3) at 30 days after
treatment with DTX/FA-PEG-MWCNTs
was 57.0 � 3.56 compared withnontargeted MWCNTs and free drug
[41]
Folic acid and
estrone
Folate and
estrogen
receptors
DOX MCF-7 cells Balb/C mice DOX/ES-PEG-MWCNTs showed
significantly longer survival span (43
days) than DOX/FA-PEG-MWCNs (42days), DOX/PEG-MWCNTs (33 days), or
free DOX (18 days)
[95]
www.drugdiscoverytoday.com 9
Reviews�KEYNOTEREVIEW
REVIEWS Drug Discovery Today � Volume 00, Number 00 �December 2015
DRUDIS-1717; No of Pages 13
TABLE 1 (Continued )
Conjugate
moieties/ligand
Receptors Chemotherapeutic
agent
Cell lines used In vivo model Outcomes Refs.
Galactosylatedchitosan
Asialo-glycoproteinreceptor
DOX HepG2 cells Male nude mice Size of tumor in O-CNTs-LCH-DOX-treated mice smaller compared with
mice treated with free DOX
[28]
HA Hyaluronatereceptor
DOX HeLa andL929 cells
Not performed Percentage of HeLa cells uptakingMWCNT/PEI–FI–HA was seven times
more than that of L929 cells; they
exhibited less cytotoxicity compared
with HeLa cells
[86]
MWCNT – DOX – Not performed Sustained release pattern [11]
PEGylated MWCNT – Oxaliplatin HT29 cell Not performed Cytotoxicity of MWCNT-PEG-oxaliplatin
to HT-29 was less compared with
oxaliplatin alone and MWCNT-oxaliplatin
[79]
Vitamin E TPGS LDL receptors DOX MCF-7 cells Balb/C mice Higher fluorescence intensity in
qualitative and quantitative cell uptakeobserved for DOX/TPGS-MWCNTs
(78.72%) compared with DOX/MWCNTs
(62.46%) and free DOX (58.15%). DOX/
TPGS-MWCNTs nanoconjugate alsoshowed longer survival span (44 days,
P < 0.001) than DOX/MWCNTs (23
days) or free DOX (18 days)
[43]
Review
s�K
EYNOTEREVIEW
destabilization; (ii) dissociation via collapse or swelling (in the
case of liposomes); and (iii) pH-dependent changes in the parti-
tion coefficient between the drug and the carrier system [81].
The ultimate goal is to design, fabricate, and evaluate pH-re-
sponsive targeted delivery systems that are capable of releasing
the precise quantities of drug payload in the tumor microenvi-
ronment. Researchers are continuously trying to develop such
systems by engineering nanocarrier systems that are more sensitive
to releasing their payload under mild acidic conditions; that is, as
close to the lysosomal pH as possible to improve their overall
efficacy. Engineered PEGylated CNTs, known as ‘stealth’ CNTs,
are an alternative that could provide significant improvements in
cancer therapy. Additionally, CNTs can be engineered with appro-
priate moieties to target specific cell surface receptors, such as those
for transferrin, folate, epidermal growth factor, and so on.
The dispersion characteristics of various functionalized MWCNTs
at 0.05 mg/mL concentration in different pH (4.0, 7.0 and 9.0) media
have also been investigated [84]. The order for stability of dispersion
in deionized water was: mannosylated MWCNTs > carboxylated
MWCNTs > amine-modified MWCNTs > purified MWCNTs > pris-
pristine MWCNTs. The better stability of carboxylated MWCNTs
compared with the amine-modified MWCNTs was attributed to the
greater ionization at pH 7.4, whereas mannosylated MWCNTs
showed stable dispersion because of the enhanced hydrophilicity
of CNTs, which were also analyzed at different pH (4, 7.4, and 9)
[82,83]. DOX release from alginate-SWCNTs (ALG-SWCNTs) and
CHI/ALG-SWCNTs was pH triggered and stable in PBS at pH 7.4 at
37 8C, and appreciable release of DOX was observed over a 72-h
period in the reduced pH microenvironment of cancerous tissue [84].
Lu et al. studied pH-controlled DOX delivery using DOX-FA-
MN-MWCNTs at 37 8C in PBS at pH 5.3 and 7.4 and found a pH-
triggered response. DOX was released in a slow and controlled
manner at pH 7.4 to the extent of 14%, which was significantly less
than at pH 5.3 (71%) because of the weakening of the hydrogen
bonds between DOX and MWCNTs. The noncovalent attachment
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon ndx.doi.org/10.1016/j.drudis.2015.11.011
10 www.drugdiscoverytoday.com
of DOX to the surface-engineered MWCNTs involves hydrogen
bonds between the –COOH of MWCNTs and the –OH of DOX, and
between the –OH of MWCNTs and the –OH of DOX, and the
degree of hydrogen bond interaction is a function of pH. Finally,
the authors also suggested that FA-MN-MWCNTs are a promising
delivery vehicle for anticancer agents because of their high drug
loading and the pH-sensitive release of DOX [52].
Depan and Mishra described a transformative approach to CNT
synthesis and demonstrated the efficacy of a hybrid nanostructured
carrier using PE-b-PEG and SWCNTs. The hybrid nanostructured
carrier was characterized by DOX molecules anchored to disk-
shaped polymer crystals within the long axis of the nanotubes.
The release of DOX was greater at 40 8C compared with at 37 8C.
Temperature affects the segmental mobility of the PE-b-PEG chains,
resulting in enhanced drug release. The authors also suggested that
the difference in DOX release at pH 5.3 and 7.4 was related to the
difference in the swelling capability of the PE-b-PEG polymer at
those pH. The swelling and relaxation of polymeric macromolecular
chains was less under physiological pH and temperature conditions,
resulting in a low concentration of DOX release. By contrast, at
low pH (5.3), the hydrogen bonding interaction between DOX and
the PEG-b-PEG polymer weakened and a higher amount of DOX
was released [58]. Thus, it appears that CNTS enable the delivery
of bioactives in a pH-responsive and/or pH-triggered manner.
Several attempts have been made to develop safe and effective
CNT-based nanomedicines for cancer therapy as well diagnostic
and imaging purposes [85]. PEI-modified MWCNTs after conjuga-
tion with hyaluronic acid (HA)- and FITC-bearing DOX
(MWCNTs/PEI-FITC-HA/DOX) were developed and characterized
using different techniques and the complex was found to be stable
[86]. The schematic representation of synthesis of MWCNTs/PEI-
FITC-HA/DOX is shown in Fig. 5a, while Fig. 5b shows that the pH-
dependent in vitro DOX release rate from MWCNT/PEI-FI-HA/DOX
at pH 5.8 (i.e., tumor cell microenvironment) was higher than pH
7.4. Fig. 5c,d shows that the fluorescence signal within HeLa cells
anotubes and bioactives: a drug delivery perspective, Drug Discov Today (2015), http://
Drug Discovery Today � Volume 00, Number 00 �December 2015 REVIEWS
DRUDIS-1717; No of Pages 13
Reviews�KEYNOTEREVIEW
was significantly higher (seven times) than in normal L929 cells at
a 2 MM concentration. MWCNT/PEI-FITC-HA/DOX was internal-
ized through CD44-mediated endocytosis.
Table 1 summarizes the use of various multifunctional CNTs
after decoration with targeting, imaging, and biofunctional chem-
ical moieties after proper functionalization in oncology to develop
safe and effective nanomedicines. The various bioactives delivered
through functionalized CNTs for pharmaceutical and biomedical
applications were recently reviewed elsewhere [7].
Limitations to the use of CNTs as bioactive deliveryvehicleThe technical limitations in the use of CNTs in biomedical appli-
cation are their inherent hydrophobic nature, insolubility, and
bundling and/or aggregation behavior [87,88]. These major hur-
dles associated with pristine CNTs could be overcome by engineer-
ing or surface decoration; that is, functionalization makes CNTs
soluble and minimizes their inherent toxicities. Numerous studies
based on in vitro, ex vivo, and in vivo systems indicate that surface-
engineered CNTs have enhanced therapeutic efficacy in diseases
such as AIDS, malaria, cancer [50], leishmaniasis [83] and TB, but
only a few studies have reported on their potential outcomes in
clinical and preclinical use.
Concluding remarks and future perspectiveCNTs are promising, safe, and effective biomaterials for devel-
opment as nanomedicines. The progress of engineered CNTs
Please cite this article in press as: Mehra, N.K., Palakurthi, S. Interactions between carbon ndx.doi.org/10.1016/j.drudis.2015.11.011
toward clinical and preclinical trials will depend upon the
outcome of safety, efficacy, and toxicological studies of CNTs.
One major hurdle is that, in a 3-(4,5-dimethylthiazol-2-yl)-2,
5-diphenyltetrazolium bromide (MTT) assay, MTT itself binds
to CNTs (quenching its fluorescence), which could lead to the
mis-analysis of toxicological results [89]. The major physico-
chemical and toxicity limitations could be addressed by conju-
gating CNTs with targeting moieties, or PEG chains, which
render them more biocompatible and nonimmunogenic. In
our view, multifunctional CNTs will continue to received signif-
icant research attention because of their unique physicochemi-
cal properties in targeted and controlled drug delivery. Although
no CNT-based drug product is currently on the market, engi-
neered CNTs are now at the crossroads of the proof-of-principle
concept and are being developed as preclinical candidates for
a variety of biomedical applications. The presence of various
amorphous and metallic impurities of pristine CNTs limits
their clinical applications because of their inherent toxicity.
Researchers are continually exploring various options to over-
come such problems by using functionalization, including
PEGylation. Apart from their interactions with bioactives, the
physicochemical factors of CNTS, such as their length, diameter,
and type, also influence their safety and efficacy. The variety
of interactions between CNT and the bioactivates discussed
here could serve as a reference for the development of multi-
functional hybrid nanotubes as carriers for biomedical applica-
tions.
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2 Chakrabarti, M. et al. (2015) Carbon nanomaterials for drug delivery and cancer
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