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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!