How Nanostructured Materials Will
Make Better Computers, Stronger
Bridges, Cure Cancer and Reduce the
Appearance of Fine Lines
and Wrinkles
Diandra L. Leslie-Pelecky
Department of Physics & Astronomy
Center for Materials Research & Analysis
University of Nebraska
Supported by the National Science Foundation MRSEC program,
Nebraska Research Initiative and the National Institutes of Health
Acknowledgements
UNL
Marco Morales
Kishore Sreenivasan
David Schmitter
Ray Lemoine
Steve Wignall
Hai Nguyen
Shannon Fritz
Michelle Strand
Collaborators
• V. Labhasetwar
(UNMC)
• M. Boska
• R. Kraus, Jr.
• M. Espy
(UNMC)
(Los Alamos)
(Los Alamos)
 T. Jain
 S. Sahoo
Outline
• 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
Nanotechnology
Why?
Why Now?
What is ‘Nano’?
Nano = one billionth
Nanometer = 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 – 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?
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
Grand Challenges
• 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
Nanotechnology Dollars
Agency
2004
Estimate
2003
Actual
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%
862
961
982
2%
TOTAL ($M)
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
Magneti
Paramagnetism
H
H=0
H
M
H
H=0
Ferromagnetism
H
H=0
H
M
H
H
Hysteresis Loop
M
Remanent
Magnetization, Mr
Saturation
Magnetization, Ms
Coercivity, Hc
H
Magnetic Periodic Table
1
H
2
He
3
Li
4
Be
11
Na
12
Mg
19
K
20
Ca
Red = Ferromagnetic
Blue = Antiferromagnetic
21
Sc
22
Ti
23
V
24
Cr
25
Mn
312 K
96 K
26
Fe
27
Co
1043 K 1390 K
28
Ni
5
B
6
C
7
N
8
O
9
F
10
Ne
13
Al
14
Si
15
P
16
S
17
Cl
18
Ar
29
Cu
30
Zn
31
Ga
32
Ge
33
As
34
Se
35
Br
36
Kr
629 K
37
Rb
38
Sr
39
Y
40
Zr
41
Nb
42
Mo
43
Tc
44
Ru
45
Rh
46
Pd
47
Ag
48
Cd
49
In
50
Sn
51
Sb
52
Te
53
I
54
Xe
55
Cs
56
Ba
57
La
72
Hf
73
Ta
74
W
75
Re
76
Os
77
Ir
78
Pt
79
Am
80
Hg
81
Tl
82
Ph
83
Bh
84
Po
85
At
86
Rm
87
Fr
88
Ra
89
Ac
58
60
Ce
Nd
13 K
59
Pr
60
Nd
19 K
61
Pm
62
60
Sm
Nd
63
60
Eu
Nd
64
Gd
65
Tb
66
Dy
67
Ho
68
Er
69
60
Tm
Nd
70
Yb
71
Lu
105 K
90 K
85 20
56 K
90
Th
91
Pa
92
U
93
Np
94
Pu
95
Am
100
Fm
101
Md
102
No
103
Lr
293 K 229 221 179 85 132 20
96
Cm
97
Bk
98
Cf
99
Es
Nanomagnetism
Why are Magnets 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 Particles
N spins, each of
moment m
RSD
‘Superspin’ of
moment Nm
36 AK

mo M s2
Single domain radius:
6 nm (Fe)
764 nm (SmCo5)
HC vs. Grain Size
Coercivity (A/cm)
100
Herzer, Scripta Met.
33, 1741 (1995)
1/D
10
1
D6
Fe93.5Si6.5
nc
0.1
Fe50Ni50
0.01
Permalloy
0.001
1 nm
1 mm
D
1 mm
Magnetism and Medicine
• 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 Scales
pollen
Gene (width)
0.1 nm
1 nm
10 nm
Bacteria
100 nm
Viruses
DNA
1 mm
10 mm
Cells
Proteins
Aspirin
Molecule
Diameter
of human
hair
100 mm
Biomedical Applications of
Magnetic Nanoparticles
• Magnetic imaging
• Magnetic heating
(Hyperthermia)
• Targeted drug delivery
• Detection/purification/isolation
• Manipulation
Leslie-Pelecky and Labhasetwar, Nanobiomagnetics in Advanced
Magnetic Nanostructures, ed. Sellmyer and Skomski, Kluwer, New
York (2006)
Magnetic Sorting
Goal: Separate/detect/isolate one type
of cell from others, often when the target
is present in very small quantities
Magnetic Sorting, Detection
Functionalize nanoparticles
O
R
O-
O-
O
Ligand
Magnetic Sorting
Add to sample
Cells
Magnetic Sorting
Magnetic nanoparticles bond with
targeted cells
Magnetic Sorting
Retain desired cells by applying a
magnetic field
Magnetic Sorting/Detection
Probe DNA
polymer
GMR
GMR
GMR
GMR
GMR
GMR
GMR
GMR
GMR
SiO2
Analyte DNA
+ biotin
Wash
unbound
DNA away
Streptavidin
+
magnetic
particle
GMR
GMR
GMR
• High sensitivity
• Multiple analytes
at one time
• Hand-held
• Lightweight
• Fast
• Potential for
single-bead
detection
Hand-Held Analysis
Seahawk's new
veterinary
diagnostic system is
based on the Naval
Research
Laboratory's
patented Bead
ARray Counter
(BARC) for
microassays
Hyperthermia
• 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
Targeted Drug
Delivery
Drug Delivery: Challenges
•Patients don’t (or can’t) take
drugs correctly
•Many drugs are highly toxic, even
in small amounts
•Systemic biodistribution
•Pharmacokinetic variability
Drug Delivery
• Drug molecules embedded in
biodegradable polymer
• Drug is released as polymer
degrades
• Time-release
• Deliver multiple drugs
• Systemic biodistribution
Magnetic Targeting
Use a magnet to direct nanoparticles to
desired location
Cancer 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
Issues
•Drug-loading capacity
•Release profile
•Aqueous dispersion stability
•Circulation time
•Biocompatibility
•Magnetic properties/targeting
•Retention
•Biodistribution/elimination of NPs
Iron-Oxide Magnetically Targeted
Drug Delivery System
• 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
Iron-Oxide Magnetically Targeted
Drug Delivery System
Pluronic®
:
Hydrophilic – Hydrophobic – Hydrophilic
Phagocyte-resistant (increases circulation time)
Available in a variety of molecular weights
+
=
Nanoparticle Structure
X-Ray Diffraction
Magnetite
Maghemite
300
100 nm
200
100
40
0
20
30
40
50
60
2 q (Degree)
70
Average XRD grain size = 9.3 ( 0.8) nm
Number of particles
Intensity (a.u.)
400
30
20
10
0
5
10 15
Diameter (nm)
Drug 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
Drug-Loaded Magnetic NPs
Added drug
solution
Magnetic
separation
Ethanol
evaporation
N
Drug
Pluronic®-Oleic acid
coated iron-oxide
nanoparticles
S
• 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.
Molecular Pharmaceutics 2, 194-205 (05)
J. Appl. Phys. 97, 10Q905 (05)
DOX Release from Iron Oxide
Nanoparticles
Drug Released (%)
100
80
60
40
20
0
0
5
10
15
20
Time (Day)
25
30
Drug Uptake: MCF-7
DOX-Sol.
DOX-Np
2 Hrs.
24 Hrs.
48 Hrs.
NCI Alliance for Nanotechnology
Stroke 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 9899% of people
 If indicated, must be administered within
three hours of stroke and may have serious
side effects
MRI of a Stroke
• Mouse stroke
model
• Magnet applied to
top of head
• Nanoparticles
segregate in
damaged region
• Improves
identification of
injured regions
• Can deliver antifree-radicals
Fabricating HighMagneticMoment
Nanoparticle
Fluids
J. Chem. Ed. 76, 880 (99)
Magnetic Targeting
F  M  H
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
Inert Gas Condensation into
Fluids
Cooled Reservoir
Cluster Deposition
R. Lemoine, S. Remboldt, M. Strand
Magnetic Fluid Deposition System
R. Lemoine, S. Remboldt, M. Strand, S. Wignall
Advantages
• 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 Fluids
Number of particles
7
6
Co
5
4
3
2
1
40
45
Diameter (nm)
0.001
Co Fluid
T = 100 K
0.000
0.003
0.002
M (emu/g)
0
M (emu/g)
42  3 nm
Co Fluid
T = 100 K
0.001
0.000
-0.001
-0.001
-0.002
-0.003
-20000
-10000
0
10000
20000
H (Oe)
-1000 -750 -500 -250
0
250
H (Oe)
100 nm
500
750 1000
Fe Nanoparticle Fluids
1.0
M/Ms
0.5
0.0
-0.5
Fe
-1.0
-10000 -5000
Number of particles
30 nm
7
6
5
4
3
2
1
0
0
5000
H (Oe)
Mean size: 18 ± 2 nm
15
20
Diameter (nm)
10000
Oxidation (Fe)
M (emu/g)
0.008
Under Ar
15 min Air
2 wks Air
0.000
-0.008
T = 300 K
-10000
-5000
0
H (Oe)
5000
10000
Oxidation
Due 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 Properties
Name
Hamposyl-O
HLB
MW
10
Charge
 (mPa s)
270 amphoteric (anionic in oil)
oleylamine
8
268 cationic
Brij-92
5
356 nonionic
oleic acid
1
282 anionic
300
12
26
Oleic acid
Oleylamine
Hamposyl-O (Oleyl
Sarcosine)
same hydrophobic tail
Oleyl Ether (Brij92)
Surfactant Type
Ms/Ms(t=0) (%)
100
0 % Brij 92
80
5 % Brij 92
5 % Span20
60
5 % Hamp-O
40
20
Fe: 15 nm
Fluid: Octoil
0
5
10
t (days)
15
20
PIB-TEPA
20% PIB-TEPA
100
Burke, Chem Mater 14, 1572 (02)
PIB=polyisobutylene
MS(t)/Ms(t=0)
80
60
40
20
0
0
5
10
15
20
25
t (days)
TEPA = tetraethylenepentamine
30
35
40
High-Moment Magnetically
Targeted Drug Delivery System
Replace 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
Nanotechnology
Benefits
Concerns
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 Goo
1986: 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 Nanotechnology
From “Prey” by Michael Crichton
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...
Popular Nanotechnology
From “Prey” by Michael Crichton
Jack 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.
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.
Nanomyths
“…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 selfpropagating, self-replicating ... is just
not going to happen as far as I know."
Héctor Abruña, Cornell University, about Prey
Nanomyths
“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 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 2003
• 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".
"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?”
Grey Goo in Print
Thurs and Hilgartner, Cornell U.
Grey Goo Gone: Drexler
• 2004: Drexler says he failed to anticipate
the extent to which his grey goo
scenario would capture the public's
imagination.
"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’”
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
Nanotechnology
For Sale!
Chewy 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
Cosmetics
Size
active ingredient
likes water
(hydrophillic)
biodegradable shell
Pores
30,000 nm – 50,000 nm
10-100 nm
skin cells
Added bonus: At this size, suspensions are translucent!
$12.95
Buckyballs in Skin Cream
• Zelens Fullerene C-60 Face Cream
• Buckyballs have “remarkable”
antioxidant properties
• $250/jar
Hitting 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 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 stainresistant ‘nanopants’
Improving 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 Cleaning
• 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 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.
Conclusions
• 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!