How Nanostructured Materials Will Make Better Computers, Stronger Bridges, Cure Cancer and Reduce the Appearance of Fine Lines and Wrinkles

Supported by the National Science Foundation MRSEC program, Nebraska Research Initiative and the National

Institutes of Health

Diandra L. Leslie-PeleckyDepartment of Physics & Astronomy

Center for Materials Research & Analysis

University of Nebraska

AcknowledgementsAcknowledgementsUNLMarco Morales Hai NguyenKishore SreenivasanDavid Schmitter Shannon FritzRay LemoineSteve Wignall Michelle Strand

Collaborators• V. Labhasetwar (UNMC)

T. Jain S. Sahoo

• M. Boska (UNMC)• R. Kraus, Jr. (Los Alamos)• M. Espy (Los Alamos)

OutlineOutline• Nanotechnology: What and Why?

• What is nanomedicine?

• Overview of magnetic nanoparticle applications in medicine

• Our work Targeted drug delivery Stoke treatment/diagnosis Making a better nanoparticle for

magnetic targeting

• Conclusions

NanotechnologNanotechnologyy

Why?Why Now?

What is ‘Nano’?What is ‘Nano’?

Nano = one billionthNanometer = one billionth

of a meter

•About ten times the size of an individual atom.

•There are as many nanometers in an inch as there are inches in 400 miles.

Feynman – 1959 – Feynman – 1959 – Caltech Caltech

“…let us say that there are some 24 million volumes of interest in the world. ...I have assumed that each of my 24 million books is as big as an Encyclopedia volume, and have calculated, then, how many bits of information there are (1015). For each bit I allow 100 atoms. And it turns out that all of the information … can be written in this form in a cube of material one two-hundredth of an inch wide -- which is the barest piece of dust that can be made out by the human eye. So there is plenty of room at the bottom!

Why Nano?Why Nano?Nanoscale materials can have

properties that are unrealizable in bulk materials

Making a material nanoscale can change its

• Melting temperature• Magnetization• Ability to hold charge

• Structure• Chemical reactivity• … among other

things

Clinton – Caltech - 2000 Clinton – Caltech - 2000

• Containing the entire contents of the Library of Congress in a device the size of a sugar cube;

• Making materials and products from the bottom-up, that is, by building them up from atoms and molecules. (less material and less pollution);

• Developing materials 10 times stronger than steel, but a fraction of the weight;

• Improving the computer speed and efficiency of minuscule transistors and memory chips by factors of millions;

• Detecting cancerous tumors that are only a few cells in size using nanoengineered contrast agents;

• Removing the finest contaminants from water and air => cleaner environment and potable water at an affordable cost

Grand Challenges

Nanotechnology DollarsNanotechnology Dollars

U.S. nanotechnology R&D will reach nearly $3.3 billion in 2007

Commercial market ~10 X to 100 X as big as the R&D market

Agency 2003

Actual2004

Estimate 2005

Proposed% Change,

2004 to 2005

NSF 221 254 305 20%

DOD 322 315 276 -12%

DOE 134 203 211 4%

HHS (NIH) 78 80 89 11%

DOC (NIST) 64 63 53 -16%

NASA 36 37 35 -5%

USDA 0 1 5 400%

EPA 5 5 5 0%

DHS (TSA) 1 1 1 0%

DOJ 1 2 2 0%

TOTAL ($M) 862 961 982 2%

MagnetiMagnetimmss

ParamagnetismParamagnetism

M

H

H = 0H

H

H = 0

FerromagnetismFerromagnetism

H = 0H

H

H

M

H

H

M

Coercivity, Hc

RemanentMagnetization, Mr

SaturationMagnetization, Ms

Hysteresis LoopHysteresis Loop

Red = FerromagneticBlue = Antiferromagnetic

2He

1H

86Rm

85At

84Po

83Bh

82Ph

81Tl

80Hg

79Am

78Pt

77Ir

76Os

55Cs

56Ba

57La

72Hf

73Ta

74W

75Re

10Ne

3Li

4Be

5B

6C

7N

8O

9F

18Ar

11Na

12Mg

13Al

14Si

15P

16S

17Cl

54Xe

37Rb

38Sr

39Y

40Zr

41Nb

42Mo

43Tc

44Ru

45Rh

46Pd

47Ag

48Cd

49In

50Sn

51Sb

52Te

53I

87Fr

88Ra

89Ac

71Lu

70Yb

61Pm

59Pr

64Gd

293 K

60Nd

19 K

60Nd

65Tb

229 221

66Dy

179 85

67Ho

132 20

68Er

85 20

60Nd

13 K

58Ce

60Nd

105 K

62Sm

60Nd90 K

63Eu

60Nd56 K

69Tm

36Kr

24Cr

312 K

19K

20Ca

21Sc

22Ti

23V

30Zn

31Ga

32Ge

33As

34Se

26Fe

1043 K

27Co

1390 K

28Ni

629 K

25Mn96 K

25Mn

35Br

29Cu

90Th

91Pa

92U

93Np

94Pu

95Am

96Cm

97Bk

100Fm

101Md

102No

103Lr

98Cf

99Es

Magnetic Periodic Magnetic Periodic TableTable

NanomagnetismNanomagnetism

Why are Magnets Why are Magnets Important?Important?

There are over three dozen magnets in an automobile!

defogger motor, temperature control, speakers, lumbar support, sunroof motor, head rest motor, tape drive motor, windshield washer pump, gauges, cruise control, mirror motors, liquid level indicators, electric power steering, electric power sensor, economy and pollution control, headlight door motor, ignition system, coolant fan motor, starter motor, windshield wiper motor, throttle and crankshaft position sensors, heat and air conditioner motor, traction control, antennae lift motor, seat adjust motors, seat belt motor, chip collector, fuel pump motor, suspension systems, four-wheel steering, antiskid sensor and motor, door lock motor, door gasket AND MORE!!!

Single Domain Single Domain ParticlesParticles

N spins, each of moment

‘Superspin’ of moment N

2

36SD

o s

AKR

M

Single domain radius: 6 nm (Fe) 764 nm (SmCo5)

HHCC vs. Grain Sizevs. Grain Size

Herzer, Scripta Met. 33, 1741

(1995)

1 nm 1 m 1 mm

1/D

D6

0.001

0.01

0.1

1

10

100

Coerc

ivit

y (

A/c

m)

nc

Fe93.5Si6.5

Fe50Ni50

Permalloy

D

Magnetism and Magnetism and MedicineMedicine• Iron and living things

Many animals use magnetic fields to navigate

Synthesize hemoglobin Role of iron in neurodegenerative disease

• Medical applications Removal of iron splinters, shrapnel, etc. Holding prosthetics Guiding instruments through the body MRI

Biological Length Biological Length ScalesScales

Proteins

Viruses

Cells

0.1 nm 1 nm 10 nm 100 nm 1 m 10 m 100 m

Gene (width) Bacteria

DNA

Diameter of human

hair

pollen

Aspirin Molecul

e

Biomedical Applications Biomedical Applications of Magnetic of Magnetic NanoparticlesNanoparticles•Magnetic imaging•Magnetic heating (Hyperthermia)

•Targeted drug delivery•Detection/purification/isolation

•ManipulationLeslie-Pelecky and Labhasetwar, Nanobiomagnetics in Advanced Magnetic Nanostructures, ed. Sellmyer and

Skomski, Kluwer, New York (2006)

Magnetic SortingMagnetic Sorting

Goal: Separate/detect/isolate one type of cell from others, often when the target is present in very small

quantities

Magnetic Sorting, Magnetic Sorting, DetectionDetectionFunctionalize nanoparticles

R

Ligand

O

OO-O-

Magnetic SortingMagnetic SortingAdd to sample

Cells

Magnetic SortingMagnetic SortingMagnetic nanoparticles bond with targeted cells

Magnetic SortingMagnetic SortingRetain desired cells by applying a magnetic field

Magnetic Magnetic Sorting/DetectionSorting/Detection

polymer

SiO2

Probe DNA

GMR GMRGMR

Analyte DNA + biotin

GMR GMRGMR

Wash unbound

DNA away

GMR GMRGMR

Streptavidin+

magnetic particle

GMR GMRGMR

•High sensitivity•Multiple

analytes at one time

•Hand-held•Lightweight•Fast•Potential for

single-bead detection

Hand-Held AnalysisHand-Held Analysis

Seahawk's new veterinary diagnostic system is based on the Naval Research Laboratory's patented Bead ARray Counter (BARC) for microassays

HyperthermiaHyperthermia• Cancer cell growth is slowed or stopped at

42 °C - 46 °C• Magnetic materials inside the body

generate heat due to• Hysteresis• Brownian motion• Eddy currents

• Nanoparticles provide • uniform heating• non-invasive delivery• multiple treatments

• Human clinical trials in progress (Germany)

Magnetically Magnetically Targeted Drug Targeted Drug DeliveryDelivery

Drug Delivery: Drug Delivery: ChallengesChallenges•Patients don’t (or can’t) take drugs correctly

•Many drugs are highly toxic, even in small amounts

•Systemic biodistribution

•Pharmacokinetic variability

Drug DeliveryDrug Delivery

•Drug molecules embedded in biodegradable polymer

•Drug is released as polymer degrades

•Time-release•Deliver multiple drugs•Systemic biodistribution

Magnetic TargetingMagnetic TargetingUse a magnet to direct

nanoparticles to desired location

Cancer DrugsCancer Drugs•Anti-cancer drugs have high nonspecific toxicities

•Most anti-cancer drugs are hydrophobic

•Cancer cells can grow resistant to drugs; simultaneous use of multiple drugs becoming necessary

IssuesIssues•Drug-loading capacity•Release profile•Aqueous dispersion stability•Circulation time•Biocompatibility•Magnetic properties/targeting•Retention•Biodistribution/elimination of NPs

Iron-Oxide Magnetically Iron-Oxide Magnetically Targeted Drug Delivery Targeted Drug Delivery SystemSystem• Iron oxides are biocompatible

and magnetic

•Oleic acid is used widely for steric stabilization of iron-oxide nanoparticles during fabrication and for suspension in non-polar solvents

•Problem: Oleic acid tail is hydrophobic

Pluronic® :

Hydrophilic – Hydrophobic – Hydrophilic

Phagocyte-resistant (increases circulation time)Available in a variety of molecular weights

+ =

Iron-Oxide Magnetically Iron-Oxide Magnetically Targeted Drug Delivery Targeted Drug Delivery SystemSystem

Average XRD grain size = 9.3 ( 0.8) nm

X-Ray Diffraction

5 10 150

10

20

30

40

Nu

mb

er

of

part

icle

s

Diameter (nm)

100 nm

MagnetiteMaghemite

Nanoparticle StructureNanoparticle Structure

20 30 40 50 60 700

100

200

300

400

Inte

nsi

ty (

a.u

.)

2 (Degree)

Drug LoadingDrug Loading•Chemical Attachment

Chemically conjugated to magnetic np coating Ionically bound to outer layer

•Disadvantages Chemically complex Multiple steps Limited loading capacity Bound drug dissociates within hours

•Good dispersibility/stability in aqueous medium•Drug is partitioned, not chemically attached•Loading with 5.4 wt. % of paclitaxel or 8.2 wt. %

doxorubicin, or a combination•Sustained release over ten days under in vitro

conditions was observed.

Drug-Loaded Magnetic NPsDrug-Loaded Magnetic NPs

N S

Magnetic separation

Added drugsolution

Ethanol evaporation

Drug Pluronic®-Oleic acid coated iron-oxide nanoparticles

Molecular Pharmaceutics 2, 194-205 (05)J. Appl. Phys. 97, 10Q905 (05)

DOX Release from Iron Oxide DOX Release from Iron Oxide NanoparticlesNanoparticles

0 5 10 15 20 25 300

20

40

60

80

100D

rug

Rel

ease

d (

%)

Time (Day)

Drug Uptake: MCF-7Drug Uptake: MCF-7

DOX-Np

DOX-Sol. 48 Hrs.24 Hrs.2 Hrs.

NCI Alliance for NCI Alliance for NanotechnologyNanotechnology

Stroke Therapy/DiagnosisStroke Therapy/Diagnosis• Stroke is

Third leading cause of death in developed countries

Leading cause of major adult disability.

• Major injury to brain not due to loss of blood circulation is due to reperfusion injury

• Few therapies exist Those that do are counter-indicated for 98-99% of

people If indicated, must be administered within three

hours of stroke and may have serious side effects

MRI of a StrokeMRI of a Stroke• Mouse stroke model• Magnet applied to

top of head• Nanoparticles

segregate in damaged region

• Improves identification of injured regions

• Can deliver anti- free-radicals

Fabricating Fabricating High-High-Magnetic-Magnetic-Moment Moment Nanoparticle Nanoparticle FluidsFluids

J. Chem. Ed. 76, 880 (99)

Magnetic TargetingMagnetic Targeting

Two Primary Issues• Fe nanoparticles oxidize rapidly

• Use surfactants to prevent oxidation

• Functionalization can change magnetic moments significantly

• Therapeutic agents

• Protective coatings

• Targeting molecules

• Oxidation protection

F M H

Inert Gas Condensation Inert Gas Condensation into Fluidsinto Fluids

Cooled Reservoir

Cluster DepositionCluster Deposition

R. Lemoine, S. Remboldt, M. Strand

Magnetic Fluid Deposition Magnetic Fluid Deposition SystemSystem

R. Lemoine, S. Remboldt, M. Strand, S. Wignall

AdvantagesAdvantages

• Any sputterable material may be used, including alloys

• Reactive sputtering allows oxides, nitrides, hydrides

• Surfactant may be chosen independently of NP size

• UHV environment

Cobalt Nanoparticle Cobalt Nanoparticle FluidsFluids

100 nm

42 3 nm

40 450

1

2

3

4

5

6

7

Num

ber

of

part

icle

s

Diameter (nm)

Co

-1000 -750 -500 -250 0 250 500 750 1000

-0.001

0.000

0.001

-20000 -10000 0 10000 20000-0.003

-0.002

-0.001

0.000

0.001

0.002

0.003

M (

em

u/g

)

H (Oe)

Co FluidT = 100 K

M (

emu

/g)

H (Oe)

Co FluidT = 100 K

Mean size: 18 ± 2 nm

-10000 -5000 0 5000 10000-1.0

-0.5

0.0

0.5

1.0

H (Oe)

Fe

M/M

s

Fe Nanoparticle FluidsFe Nanoparticle Fluids

15 2001234567

Num

ber

of

part

icle

s

Diameter (nm)

30 nm

Oxidation (Fe)Oxidation (Fe)

-10000 -5000 0 5000 10000

-0.008

0.000

0.008

T = 300 K

M (

em

u/g

)

H (Oe)

Under Ar 15 min Air 2 wks Air

OxidationOxidationDue to• diffusion of oxygen through carrier liquid• oxygen in carrier liquid• oxygen in surfactant

Surfactant Properties• hydrophilic-lipophilic balance• charge of headgroup• conformation• branching/saturation• surface area occupied• type of attachment to particle

Surfactant PropertiesSurfactant PropertiesName HLB MW Charge (mPa

s)

Hamposyl-O 10 270 amphoteric (anionic in oil) 300

oleylamine 8 268 cationic 12

Brij-92 5 356 nonionic

oleic acid 1 282 anionic 26

Oleic acid

Oleylamine

Hamposyl-O (Oleyl Sarcosine)

Oleyl Ether (Brij-92)

same hydrophobic tail

Surfactant TypeSurfactant Type

0 5 10 15 20

20

40

60

80

100

t (days)

0 % Brij 92

5 % Brij 92

5 % Span20

5 % Hamp-O

Ms/M

s(t

=0)

(%)

Fe: 15 nmFluid: Octoil

PIB-TEPAPIB-TEPA

PIB=polyisobutylene

TEPA = tetraethylenepentamine

Burke, Chem Mater 14, 1572 (02)

0 5 10 15 20 25 30 35 400

20

40

60

80

100

MS(t

)/M

s(t

=0

)

t (days)

20% PIB-TEPA

High-Moment Magnetically High-Moment Magnetically Targeted Drug Delivery Targeted Drug Delivery SystemSystemReplace iron-oxide nanoparticles in

formulation with high-moment inert-gas-condensed nanoparticles

• improved magnetic targeting• potential use as MRI contrast agent• potential use in hyperthermia• biotoxicity tests

NanotechnologyNanotechnology

BenefitsConcerns

What if…?What if…?… someone said, 'Here's a

new technology that's going to change the world, but it will kill

50,000 people a year.'

Would you be in favor of it?

Grey GooGrey Goo1986: Eric Drexler writes about fears that self-replicating nanotechnology could multiply at exponential rates, spreading and crowding out everything else. “We cannot afford certain

types of accidents”

Popular Popular NanotechnologyNanotechnology

High-tech whistle-blower Jack Forman used to study the behavior of efficient wild

animals--swarming bees or hunting hyena packs, for

example. He suspects his wife, who's been behaving strangely and working long hours at the

top-secret research labs of Xymos Technology, is having an

affair...

From “Prey” by Michael Crichton

Popular Popular NanotechnologyNanotechnologyJack soon finds that illicit affairs

are the least of the problems. His wife's firm has created self-

replicating nanotechnology--a literal swarm of microscopic

machines.

From “Prey” by Michael Crichton

Originally meant to serve as a military tool, the swarm has

escaped into the environment and is seemingly intent on

killing the scientists trapped in the facility.

NanomythsNanomyths“…that simply violates too many game rules as we know them in terms of energy balances and thermodynamics—all sorts of

things… To think that one could engineer something at that level, with that level of sophistication,

that is self-propagating, self-replicating ... is just not going to

happen as far as I know." Héctor Abruña, Cornell University, about Prey

NanomythsNanomyths

“The idea was that one would build little machines, and the little machines would build themselves, and there would be exponential growth, and they would crawl out of test tubes and eat the Earth. And this was, I think, from the beginning, pretty much nonsense.”

George Whitesides (Harvard)

Prince Charles 2003Prince Charles 2003

• Quotes a retired university professor saying it would be "surprising" if it did not "offer similar upsets" as thalidomide

• Calls upon the Royal Society to investigate the "enormous environmental and social risks" of nanotechnology

• Comments were broadly welcomed by scientists; however, most felt his reference to thalidomide was "inappropriate and irrelevant"

Prince Charles 2003Prince Charles 2003

"Some of the work may have fundamental benefits to society, such as enabling the construction of much

cheaper fuel-cells, or new ways of combating ill health…How are we going to ensure that proper

attention is given to the risks that may... ensue?”

• Says he never used the expression "grey goo",

• "I do not believe that self-replicating robots, smaller than viruses, will one day multiply uncontrollably and devour our planet. Such beliefs should be left where they belong, in the realms of science fiction."

• Acknowledges nanotechnology is a "triumph of human ingenuity".

Grey Goo in PrintGrey Goo in Print

Thurs and Hilgartner, Cornell U.

Grey Goo Gone: Grey Goo Gone: DrexlerDrexler

"I expected the contemplation of the broad societal impacts of nanotechnology to

cause some discomfort, but did not expect that depictions of swarms of self-

replicating nanobugs would dominate popular perceptions of advanced

nanotechnology“

“I wish I had never used the term ‘grey goo’”

• 2004: Drexler says he failed to anticipate the extent to which his grey goo scenario would capture the public's imagination.

Are There Concerns?Are There Concerns?• 2003: Two independent studies (Chiu-Wing

Lam of NASA's Johnson Space Center, and David Warheit of DuPont) find that carbon nanotubes, when directly injected into the lungs of mice, can damage lung tissue

• 2004: Eva Oberdorster (Southern Methodist University) finds that a spherical form of carbon called buckyballs caused extensive damage to the brain cells of bass

• 2005: Researchers at Rice find that the curvature of buckyballs has a large impact on whether they are toxic to cells

NanotechnologyNanotechnology

For Sale!

Chewy ChocolateChewy Chocolate• Chewing gum gets its

elasticity from polymers

• Cocoa butter causes those polymers to fall apart

• Choco'la Chewing Gum uses nanoscale crystals to incorporate the creamier texture and chocolate flavor into chewing gum.

• Sugar free• Five calories per piece

CosmeticsCosmeticsSize

likes water (hydrophillic)

10-100 nm

active ingredient

biodegradable shell

Pores30,000 nm – 50,000 nm

skin cells

Added bonus: At this size, suspensions are translucent! $12.95

Buckyballs in Skin Buckyballs in Skin CreamCream• Zelens Fullerene C-60 Face

Cream • Buckyballs have “remarkable”

antioxidant properties• $250/jar

Hitting a Home RunHitting a Home Run

• Slugger-Easton Sports Stealth CNT (carbon nanotube) technology

• The spaces between fibers in ordinary carbon fiber bats are filled with resin

• This bat has CNTs in the resin for optimized flex, responsiveness and more "kick" through the hitting zone

• $175 and up

Stain Proof FabricStain Proof Fabric• Nano-Tex nano-enhanced clothing

has fibers with tiny whiskers aligned by proprietary spines to repel liquids reduce static resist stains

without affecting texture.

In May 2005, a group of people stripped naked at an Eddie Bauer store in Chicago to protest the sale of stain-resistant ‘nanopants’

Improving Smelly SocksImproving Smelly Socks

• ARC Outdoors, ArcticShield Socks

• Incorporate 19-nanometer antimicrobial silver particles within their fibers.

• A comfortable synthetic fiber sock with permanent resistance to odor and fungus.

Nano Decreases Nano Decreases CleaningCleaning• Behr NanoGuard Paint:

Nanoadditives increase the density of water-based acrylic latex carrier and makes a harder, more durable surface that is resistant to water, mildew, stains and grease.

• Pilkington Activ Glass has a few dozen nanometers of a photoactive film that self cleans your windows.

• Now available at certain large home improvement stores

Other Possible AdvancesOther Possible Advances• Wear-resistant tires made by combining

nanometer-scale particles of inorganic clays with polymers

• Environmentally friendly dyes and pigments Nanometer-scale traps to remove pollutants from the environment and deactivate chemical warfare agents.

• Computers with the capabilities of current workstations will be the size of a grain of sand and able to operate for decades with the equivalent of a single wristwatch battery.

• Robotic spacecraft that weigh only a few pounds will be sent out to explore the solar system, and perhaps even the nearest stars.

ConclusionsConclusions• Nanotechnology offers great promise for

the future, especially in medical applications

• There are many potentially positive implications of nanotechnology in medicine

• It is critical to understand how nanomaterials behave differently than their bulk counterparts

• Swarms of nanobots intending to take over the world are not likely to be landing in Iowa anytime in the near future.

• Stay tuned!