Biomedical Nanotechnologies
And Space Medicine
Mauro Ferrari, Ph.D.
Professor, Brown Institute of Molecular Medicine
Interim Chairman, Dept. Biomedical Engineering
University of Texas Health Sciences Center,
Houston
Professor, Experimental Therapeutics,
University of Texas MD Anderson Cancer Center
Professor, Bioengineering, Rice University
President, Texas Alliance for NanoHealth
NASA Grand Rounds, Houston, March 28, 2006
Five Main Theses
„
Medical nanotech offers opportunities for
advances in space medicine
„
Nanotech enables early detection, continuous
monitoring
„
Nanotech enables the tailoring of
biodistribution, autonomous intervention
„
Nanotech in medicine must be integrated with
novel mathematical and simulation tools
„
Medical nanotech is the ultimate team sport
Disclosure & Funding Acknowledgment
„
Mauro Ferrari has a financial interest in
iMEDD, Inc. and Leonardo Biosystems, Inc.
„
Funding for the Ferrari laboratory: NCI, SAIC,
NASA, NSF, DARPA, DoD, State of Texas,
State of Ohio, Hops Street Kids Foundation
Plan for Talk – Cancer as Template
„
An overview of nanotech for
molecular diagnostics
„
Nanotech-based (imaging
and) therapeutics
aNanovectors
aNanotech-based implants
„
Reference: M. Ferrari, Cancer
Nanotechnologies,Nature
Reviews Cancer, March 2005
Cancer is the #1 killer of Americans
under 85 and a major killer worldwide
570,280 Americans will die of cancer this year
a 1,372,900 Americans this year will hear the words “you have
cancer…”
a $192 billion = Costs of cancer in 2004
More Progress is Needed to Reduce Death Rates
Death Rate Per
100,000
600
586.8
1950
2002
500
400
300
240.1
193.9 193.4
180.7
200
56.0
100
48.1
22.5
0
Heart
Diseases
Cerebrovascular Pneumonia/
Diseases
Influenza
Source: American Cancer Society.
Cancer
Mechanisms of the Cancer Process
The Six Essential Aberrations of Cancer
Evading
Apoptosis
Sustained
Angiogenesis
Self-Sufficiency in
Growth Signals
Insensitivity to
Anti-Growth Signals
Tissue Invasion
and Metastasis
Limitless Replicative
Potential
After
After Hanahan
Hanahan &
& Weinberg,
Weinberg,
Cell
Cell 100:57
100:57 (2000)
(2000)
Intervention in the Cancer Process
Prevent
BRCA-1 Mutation
Detect
Modulate
Colorectal
Cancer Screening
Tumor
MicroEnvironment
Eliminate
2005
Death due
to Cancer
Metastatic
Progression
Susceptibility
Birth
2015
Malignant
Transformation
Pre-Cancerous
Changes
Life Span
Natural
Death
Nanotechnology in Perspective
Water
Glucose
10-1
1
Antibody
10
Virus
Bacteria
Cancer cell
102
103
104
Nanometers
Nanodevices:
Nanopores
Dendrimers
Nanotubes
Quantum dots
Nanoshells
105
A period
106
Tennis ball
107
108
Nanotechnology is already in the
clinic!
„
Liposomes
„
DNA chips
„
Proteomic
nanotechnology
„
Imaging contrast
agents
„
Laboratory
equipment
„
New drugs
Contrast agent
(X-ray, MRI)
Cell
death
sensor
Cancer cell
targeting
Therapeutic
Nanotechnology for Molecular
Diagnostics
Proteomic Nanotech: Objectives
„
To use biological fluid samples (blood draw,
etc) to identify special combinations of
proteins that can be used to:
a Screen for cancer
a Identify cancer site
a Determine stage/prognostics
a Select proper therapy
a Monitor efficacy of therapeutic intervention
a Monitor side effects
Serum Proteomic Nanotechnologies Key Challenges
„ Sample
„ Low
Preparation / Fractionation
Concentration Ranges
„ Multiplexing
„ Quantitative
„ High
(Label-Free) Detection
Throughput
Molecular Signature Nanotechnologies
- Platforms
Biologically Gated Transistors (Nanowires,
Nanotubes)
„ Nanostructured Surfaces and Microparticles
for Mass Spectrometry
„ Reverse Phase Protein Microarrays (RPMA)
„ Bio-BarCode
„ Micro/Nano-Cantilevers
„ CMUS/C-Scan Nanomechanics
„
Multiplexing proteomic detection
capabilties
Nanoscale Cantilevers
Cantilevers detect
biomarkers of cancer
Cancer
cell
Proteins
Antibodies
Binding events change
cantilever shape, and
properties
Arun Majumdar, University
of California at Berkeley
Microcantilevers: Modes of operation
•
•
•
•
Analytes selected by coating
Produces stress
Bends cantilever
More adsorption produces more
bending
• Reversibly desorbs
Resonant frequency
decreases with mass
loading ΔDw
ω
Amplitude
Amplitude
Cantilever bends
due to adsorption
forces
Frequency
Frequency
Thundat, T., Chen, G.Y., Warmack, R.J., Allison, D.P., Appl. Phys. Lett., (1994)
Chen, G.Y., Thundat, T. Wachter, E. A., Warmack, R. J., “Adsorption-induced surface stress and its effects on resonance
frequency of microcantilevers,” J. Appl. Phys 77, pp. 3618-3622 (1995).
Rabbit AntiHuman PSA
DTSSP
Glass
Wu et al., (2001)
Nature Biotechnology, Vol. 19,
pp. 856-860
Au
SiNx
200
150
100
50
fPSA
Cantilever:
600 μm long,
0.65 μm thick
Cantilever:
366 μm long,
0.65 μm thick
fPSA
cPSA
fPSA
Cantilever:
200 μm long,
0.5 μm thick
0
10-2
(Thomas Thundat, ORNL)
Clinical Threshold of
PSA Concentration
(4 ng/ml)
[BSA] = 1 mg/ml
Bending (nm)
Analyte
Steady-state Deflection, hs [nm]
Cantilever Assay for PSA
10-1 100 101 102 103 104
PSA Concentration [ng/ml]
105
Bending (nm) Vs PSA concentration
Cantilevers with three different lengths immobilized with PSA antibody undergo
Bending when exposed to PSA (in presence of 1 mg/mL BSA
Surface Stress due to PSA Binding
d
h=
2
σ (1 − ν ) ⎛ L ⎞
E
Surface Stress
) 2]
Surface
Stress(mJ/m
, σ [J/m
L
0.06
⎜ ⎟
⎝d⎠
2
0.05
[BSA] == 11 mg/ml
mg/ml
[BSA]
200 μm long, 0.5 μm thick
cantilever
0.04
0.03
0.02
600 μm long, 0.65 μm thick
cantilever
0.01
366 μm long, 0.65 μm thick
cantilever
0.00
-0.01
10-2
10-1
100
101
102
103
104
fPSA Concentration [ng/ml]
Cantilever response can be expressed in surface stress –
a REQUIRED transition for mechanistic understanding
105
Key concept
„
Mathematical model required to:
aEvolve PREDICTIVE capabilities
aTailor sensor design to requirements
aEstablish scientific foundation – mechanistic
understanding of molecule/surface/molecule
interaction
„
Fundamental complexity: Integrating multiple
scales of model, from molecular to structural
(continuum)
Nanotech and the system approach to
cancer biology
Nanowire Sensor
Particles flow through
the microfluidic channel
Electrodes
Nanowire
sensor
Nanowires detect
biomarkers of cancer
Jim Heath, California Institute of
Technology, & Lee Hood, ISB
mfluidics- massively
multiplexed plumbing
for nanotechnologies
The Nanolab
Electrophysiology
HIT-T15
HIT-T15 whole-cell
whole-cell recordings
recordings
Ca+2
buffer
(2mM
EGTA)
Ca+2 buffer (2mM EGTA)
Nanowire Sensors
HIT-T15
HIT-T15cell
cellon
onchip
chip
Signatures
Signatures of
of gene
gene &
&
protein
protein expression
expression
Nanomechanics
Nanomechanics
Protein-protein
Protein-protein &
& Protein-DNA
Protein-DNA
interactions
interactions
Electrophysiology
Electrophysiology
sensors:
sensors: signatures
signatures
of
of cellular
cellular
processes.
processes.
Dendritic
Dendritic
cell
cell
Effector
Effector
TT cell
cell
Macrophage
Macrophage
Heath,
Heath,
CalTech
CalTech
Surface nanopatterning for molecular
ID & Dx
Plasma
1898.1
% Intensity
80
A
1741.7
943.0
2662.1
6638.0
3319.0
4582.5
9147.1
6598.6
0
800
10000
Mass (m/z)
Silica type B
Silica type A
2485.7
3868.5
1848.0
2863.0
30
B
2108.3
1053.2
3283.7
861.7
3519.4
4575.0
0
% Intensity
% Intensity
20
800
Mass (m/z)
9138.7
9430.3
4569.6
2485.7
1848.0
4713.2
C
2357.5
1078.81866.3 3316.3
6632.0
3868.32 4967.3
9140.6
10000
0
8919.3
9385.2
8769.3
800
Mass (m/z)
8693.4
7673.8
10000
Plasma Low Molecular Weight Proteins
capturing strategy on silica nanoparticles
A
B
1. Incubation
2. Centrifugation
C
3. Separation
4. Extraction buffer
D
5. Centrifugation
6. Separation
MALDI-TOF
Silica particle surface
Silica particle surface
with Low MW Proteins
A Incubation of human plasma with silica nanoparticles and Low Molecular Proteins adsorption
B Centrifugation and separation of plasma from nanoparticles
C Buffer assisted extraction of Low Molecular Weight Proteins from nanoparticles
DExtracted Proteins recovery and MALDI-TOF analysis
University of ‘Magna Græcia’ at Catanzaro – Italy
ROSA TERRACCIANO
University of ‘Magna Græcia’ at Catanzaro – Italy
ROSA TERRACCIANO
LOD
1760.4
90 ng/mL
1760.6
*
0
1600
% Intenity
100
1760.8
*
% Intenity
100
0
1600
2000
Mass (m/z)
1760.5
*
Mass (m/z)
RENIN
0
f
200 ng/mL
5735.3
*
6000
4450
0
g
30 ng/mL
5735.1
*
2000
6000
4450
100
d
5 ng/mL
6000
4450
100
c
10 ng/mL
0
1600
2000
Mass (m/z)
* e
100
b
30 ng/mL
0
% Intensity
% Intenity
100
2000
Mass (m/z)
500 ng/mL
% Intensity
0
1600
100
a
h
15 ng/mL
% Intensity
% Intenity
100
5734.6
% Intensity
*
5734.3
0
4450
*
Mass (m/z)
6000
University of ‘Magna
Græcia’ at Catanzaro – Italy
INSULIN
ROSA TERRACCIANO
Considering that to date the lowest
concentration for a biomarker such
as Haptoglobin-α subunit,
identificated by MS is 1000 nmol/L
our LMWP plasma enriching
approach lowered the LOD of
roughly 400-fold.
University of ‘Magna Græcia’ at Catanzaro – Italy
ROSA TERRACCIANO
Bio-BarCode (Chad Mirkin)
The bio-barcode amplification
assay. The assay uses MMPs
functionalized with mAbs that
recognize and bind ADDLs. The
ADDLs are then sandwiched
with an NP probe, modified with
double-stranded DNA and an
anti-ADDL pAb. After repeated
washing while using a magnet
to immobilize the MMPs, a
dehybridization step releases
hundreds of barcode DNA
strands for each antigen-binding
event.
Georganopoulou, Dimitra G. et al. (2005) Proc. Natl. Acad. Sci. USA 102, 2273-2276
Opportunity for Translation and
Synergy in Space Medicine
„
Early Detection and Monitoring of Disease
from Proteomic Signatures in Plasma
a Automated – no medical personnel required
a Non-Invasive
a Repeatable – time sequences possible
a No imaging equipment
a Miniaturizable analytical equipment
a Applicability to other fluids
a Linkable to autonomous therapeutics
Innovative Molecular Analysis Technologies
Nanomechanical Method for Molecular Analysis of Cancer
Specific Aim 1: To target antibody-conjugated nanoparticles to cell-surface
antigens on tissue samples specifically for ultrasound examination.
Specific Aim 2: To develop the ultrasonic system for detection of the
molecular information through preferentially immunoconjugated
nanoparticles.
Specific Aim 3: To develop and refine the DM-based model and data
analysis software, to perform quantitative and objective interpretation of the
molecular information.
Two Quantitative Approaches:
1) Characterization-Mode Ultrasound (CMUS): Mechanical Analysis
2) C-Scan Ultrasound: Attenuation Analysis
HER-2/neu Exploitation
•HER-2/neu over expressed in 20-30% of all breast cancers
•High levels of HER-2/neu receptor expression is an indicator of poor
prognosis in breast cancer patients and serves as a predictive factor
in projecting patient response to chemotherapeutics.
•Positive lymph nodes is the only prognosticator more predictive for
clinical outcome.
Molecular Analysis Strategy
Linker
= mAb (Protein G)
Breast
Cancer Cell
Iron
Oxide
Her-2/neu
Receptor
Antibody conjugated nanoparticulate bound to cognate HER2/neu tumor receptors. The
conjugated particles will serve as
mechanical/attenuation ultrasonic
contrast agents for quantitative
analysis of HER-2/neu expression.
Gate Signal
FFT
SKBR-3 Ultrasound
Cells Transducers
Magnitude of Reflection Coefficient
CMUS: Quantitative Analysis of Mechanical Contribution
Provided by Ultrasound Nanoparticle Contrast Agents
Frequency (Mhz)
Time Domain Plot
Continuum/Doublet
Mechanics Based 2-Step
Inversion Algorithm
Frequency Domain Plot
C-Scan: Quantitative Analysis of Attenuation Provided by
Ultrasound Nanoparticle Contrast Agents
Top Row: Ultrasound C-Scan Images
Bottom Row: White light photos of histology slides stained for HER-2/neu
expression
Colored Rings: Regions of interest (Both areas of expression and no expression)
Herceptin conjugated nanoparticle = Her-Con
Iso-type Matched antibody conjugated nanoparticle – ISO-Con
C-Scan: Data Table
Image Analysis Difference (IAD)
•
Mean intensity values in relation to 256 grey scale
•
IHC score assigned by pathologist and correlated to U/S IAD value
•
IAD score measured from U/S image analysis comparing the mean
intensities of HER-Con treated tissue and tissue having no treatment
C-Scan: Summary of Data
C-Scan Tissue Grading Criterion:
IAD<6 corresponds to IHC grade 0
19<IAD corresponds to grade +2
6<IAD<19 corresponds to grade +3.
Achievement
Achievement #1:
#1: We
We have
have obtained
obtained specificity
specificity == 96.8%
96.8%
Achievement
Achievement #2:We
#2:We have
have obtained
obtained 100%
100% sensitivity
sensitivity for
for the
the +3
+3 grade
grade
tissue,
tissue, and
and 87.5%
87.5% for
for the
the grade
grade 00 tissue.
tissue.
Achievement
Achievement #3:
#3: We
We have
have obtained
obtained 100%
100% sensitivity
sensitivity for
for the
the
+2
+2 grade
grade tissue.
tissue.
Transitioning to CMUS mode: Multiscale
architecture, diagnostics, and
biophysical, fouling-indifferent sensors
x2
Incidence
Reflection
glass
d
x1
tissue
glass
Waves in tissue layer
Transmission
Structure of the theory
a Body = set of nodes at finite
distances (down to nano –
thus “nano”mechanics)
a Pair of nodes = Doublet
(thus, Doublet Mechanics or
DM, or Nanomechanics) –
replaces differential volume
element of Continuum
Mechanics (CM)
a Example: H4 packing…
Data Analysis Human Breast Biopsy, Same Individual
KEY: MULTISCALE MATHEMATICAL MODEL
Continuum mechanics reconstruction:
Tumor
Density (g/cm3 )
E (Gpa)
Shear (Gpa)
attn. 1
attn. 2
Normal
T Test
mean
SD
mean
SD
0.9796
0.1304
0.0438
0.0130
0.0108
0.0788
0.0214
0.0072
0.0112
0.0036
0.8728
0.1135
0.0381
0.0000
0.0200
0.0469
0.0449
0.0152
0.0000
0.0088
P values
0.1298
0.5975
0.6046
0.1836
0.2039
Doublet mechanics reconstruction
Tumor
Density (g/cm3 )
A11 (Gpa)
A44 (Gpa)
attn. 1
attn. 2
Internodal (mm)
Normal
T test
mean
SD
mean
SD
0.8315
2.1637
0.0523
0.1457
0.1465
0.0065
0.0233
0.0571
0.0192
0.0194
0.0420
0.0011
0.8147
1.7836
0.2202
0.0675
0.0706
0.0026
0.0589
0.0626
0.0327
0.0329
0.0351
0.0008
(J. Liu and M. Ferrari, Disease Markers, 2004)
P values
0.6813
0.0015
0.0035
0.0337
0.0764
0.0091
Multifunctional Therapeutic
Nanosystems
Nanoparticles for therapeutics and
diagnostics. Key strategy
„
Providing preferential, effective concentrations of
therapeutic agents and imaging enhancers at lesion
sites, by a combination of
aMultimodal targeting, such as affinity-based +
size & shape + surface properties + remote
activation… (probabilities of localization are
additive)
aOvercoming of biological barriers, such as
endothelial, epithelial, increased osmotic
pressure, macrophage uptake, …. (probabilities
of reaching lesion are multiplicative)
aProviding co-localized combination therapy
Microfabricated Trans-Mucosal Patch
(iMEDD)
For Delivery of
Biologically Active Peptides and Proteins
Intestinal
lumen
Vasculature
N
H
......
.
.
...... ...........
..... .
.........
.........
...
......
......
.....
.
N
H
N
H
... ......
........... ...
............
.......
.........
...
N
H
.
N
H
. ....
.. .........
...........
.
Intestinal
epithelial
cells
. .. ......
. ..........
................
...........
........
.........
...
......
...
..
................
......
...........
.......................
......
..................
.....
....................
............
....................
......
............
.
Intestinal
mucin
N
H
N
H
.........
..........
........
.........
...
N
H
N
H
5. Drug passes
between cells
and enters
blood stream
Quantum dots for intracellular imaging
Marcel Bruchez, Ph.D.
Semiconductor quantum dots are being
developed for use as probes for intracellular
structures. In this study, they were used to
label the breast cancer marker Her2 on the
surface of fixed and live cancer cells, to stain
actin and microtubule fibers in the cytoplasm,
and to detect nuclear antigens inside the
nucleus. Quantum dots offer several
advantages over the organic dyes typically
used for comparable studies.
Nature Biotech., 2003, 21:41-46
Nanotech Will Enable In Vivo
and Local Imaging
Problem:
„
Cancer metastasizes before it can be
detected
Solution:
„
„
Multi-functional nanoparticles
functionalized with specific antibodies
decorate tumor cells
Subsequent imaging allows for
pinpointing of tumor cell
conglomerates
Quantum dots
Source: JAMA, Vol. 292,
No.16, p.1944-1945, 2004.
UNIVERSITY OF MICHIGAN
James Baker, M.D.
Multifunctional nano-devices based on dendritic polymer
components are developed to target neoplastic cells and
sense the earliest signatures of cancer. The dendritic
nano-devices are designed to support the specific
release of a therapeutic agent within a tumor, and
analyze the effect of the therapeutic identifying evidence
of residual disease.
Multi-functional Dendrimer
Nano-platforms
Traditional therapy
Kukowska-Latallo, Baker et al., Nanoparticle targeting of
anticancer drug improves therapeutic response in animal
model of human epithelial cancer. Cancer Research, 65
(12): 5317. (2005)
Nanoparticle therapy
Targeted-Acoustic
Nanoparticle
(250 nm)
Add Gd-DTPA
Lipid Surfactant
Targeted-MRI
Nanoparticle
Ligand
Perfluorocarbon
Add Drug
BARNES-JEWISH
HOSPITAL
Sam Wickline and Gregory M.
Lanza + KEREOS Inc.
Targeted-Therapeutic
Nanoparticle
Molecular Imaging
of Solid Tumors
ανβ3-integrin
Angiogenic
Vessel
A novel multi-modal site-directed contrast agent for sensitive and specific
detection and localized treatment of solid tumors. The agent is a patented
ligand-targeted, lipid encapsulated, non-gaseous nanoparticulate (~200
nm diameter) perfluorocarbon emulsion that may be used with at least
three common noninvasive imaging modalities: ultrasound (native
particle), magnetic resonance (gadolinium conjugated), and nuclear
imaging (radionuclide conjugated). The nanoparticles are targeted to
tumors through targeting ligands specific for unique vascular growth
factor receptors and ligands and formulated with chemotherapeutic
agents to provide localized therapy of small tumors.
Targeted Drug
Delivery
Reservoir
with cytolytic
agent
Particle
Detection
ligand
iMEDD, Inc.
Frank Martin
Carl Grove
M. Ferrari, 2000
Nanotech for multifunctional
targeted therapeutics
Nanoshells
Nanoshell
Cancer
Cancer
cell
cell
Nanoshells kill tumor
cells selectively
Jennifer West, Naomi
Halas, Rice University
Nanoshells in action
Naomi Halas and Jennifer West,
Rice University and Nanoshells, Inc.
Two tumors in a mouse are simultaneously
ablated. The colored areas (blue and yellow)
represent temperature levels conducive to
ablation. The Nanoshells injected into the
tumor in the upper left are being irradiated
from the laser on the other flank of the mouse.
Many nanoplatforms!
„
„
„
„
„
„
Liposomes, Micelles,
Solid Lipid,
Micro/nanobubbles
Dendrimers,
Dendrisomes
Lipid-encapsulated
PFC emulsions
Iron-oxide, drugable
entities
Nanoshells
Q-Dots
„
Silicon, SiO2
micro/nanoparticles
„
Biodegradable
micro/nanospheres
„
Leashed polications
„
DNA-based constructs
„
Engineered viral
particles
„
Buckeyballs
„
…..
Mathematical Model – Margination
t[s]
200
150
Time for Margination
Rc
Δρ = 1000
100
70
50
kg/m3
(Decuzzi, …, Ferrari,
Annals of Biomed Engr
2004, 2005)
30
20
15
R[nm]
50 100
500 1000
5000 10000
• The time for margination is influenced by the relative density Δρ and
electromagnetic properties (Hamaker constant A) of the particle
• A critical radius Rc exists for which the margination time is maximum
• The maximum is influenced by Δρ and A and can be tuned!
Opportunity for Translation and
Synergy with Space Medicine
„
Nanovector Therapeutics
a Engineering Biodistribution, PK, PD
a Intervention Tailored to Individual Astronaut
a Reduction of Side Effects
a Advantage in Drug Stability/Shelf Life
a Self-Administration
a Linkable to Molecular & Imaging
Diagnostics/Monitoring
a Targeting DNA Repair
Implantable Long-Term Controlled
Release System for Biomolecular
Therapeutics
Plasma Drug
Concentration
Toxicity
Therapeutic Range
Toxicity
Diminished Activity
Time
nDS1
nDS2
NanoGATE Drug Delivery Technology
Membrane holder
Donor well
Silicon
sealant
Acceptor
well
Silicon
Membrane
Release Data
• Experiments
show
a
significant deviation from
Fick’s law when the channel
height is reduced to few nm
• The release is linear for a
prolonged time interval
An Alternative Approach Based on van der
Waals law (Cosentino, ...., Ferrari, J. Phys. Chem. 2005)
„
Van der Waals (1873) equation of state
for real gases and liquids
a⎞
V
⎛
⎜ p + 2 ⎟(λ − b ) = RT , λ =
λ ⎠
n
⎝
2 a0
1
~ kT
−
ν
D=
2
mβ (1 − b0C ) mβ
Van der Waals eq. takes into
account the electrical
interactions between
molecules and the volume
constraints.
G. PESKIR Stoch. Models, Vol. 19, N. 3, 2003, pp 383-405.
2b0
2a0 ⎞ ∂C ⎛ kT
2 a0 ⎞ ∂ 2 C
∂C ⎛ kT
1
⎟
+ ⎜⎜
−
C ⎟⎟ 2
= ⎜⎜
−
3
2
⎟
∂t ⎝ mβ (1 − b0C ) mβ ⎠ ∂x ⎝ mβ (1 − b0C ) mβ ⎠ ∂x
E (kJ/M)
(S.Pricl, Mark Cheng, C. Cosentino, M.Ferrari, to appear)
100
80
60
40
20
0
-20
-40
-60
-80
-100
0
∂ν
∂t
⎛
⎜
2b
⎜
0
= ⎜⎜ kT
3
6πrη ⎛
⎞
⎜
ν
1
−
b
⎟
⎜
⎜
0 ⎠
⎝
⎝
1
2
⎞
⎟
3
4
⎛
⎜
5
d (Å)
6
7
8
9
10
⎞
⎟
2 a ⎟⎛ ⎞ 2 ⎜
2a
⎟ 2
1
− 0 ⎟⎟⎜⎜ ∂ν ⎟⎟ + ⎜⎜ kT
− 0 ν ⎟⎟ ∂ ν
6πrη ⎝ ∂x ⎠
6πrη ⎛
2 6πrη ∂x 2
⎞
⎟
⎟
⎜
ν
1
−
b
⎜
⎟
⎟
⎜
⎟
0 ⎠
⎝
⎠
⎝
⎠
“Dial-a-release-rate”
• Essential form-identity
• Van der Waals forces yield a
saturation effect on the
Brownian motion
• Explicit reconstruction: MD
simulations underway
The “magic triad” of nanotech
„ Obtained
medically desired property
(long-term zero-order release of
biodrug)….
„ ….based
on phenomena that only
occur at nanoscale…
„…
and can be successfully and
quantitatively modeled and
MECHANISTICALLY PREDICTED
Transition to nDS2: Electronics
Onboard
Contact pad
Entry port
Anchor points
Connecting cables
Output finger
Entry flow
chamber
Nanochannels
Exit flow chamber
Anchor points
Input finger
Exit port
Electrodes
Glass top substrate
Silicon Bottom substrate
3-dimensional view of nDS2 – With integrated electrodes
Schematic view of nDS2
AFM image of nanochannel steps
SEM Images of fabricated substrate
nDS2 DC Driving of Fitz fluorescent Protein
3V voltage applied
3V, voltage reversed
Time=0
Time=0
26 sec
60 sec
46 sec
131 sec
68 sec
187 sec
nDS2 – A Universal Platform
Control Circuit
nDS2 – A Universal Platform
t2
V2
V1
t1
Pre-programmable circuit
nDS2 – A Universal Platform
nDS2 – A Universal Platform
Implantable
sensor
Schematic view of nDS2 with sensor
Battery
Sensor
Unit
Control
Circuit
nDS2
Nanochannel-Based Drug-Delivery
Implants (nDS)
„
nDS1: Passive Release
„
nDS2: Active Release – Preprogrammed
„
nDS3: Active Release – Remotely Activated
„
nDS4: Active Release – Self-regulated
a Biomolecular/Chemical/PhysicalSensor
a + Intelligence
a + Actuator
Opportunity for Translation and
Synergy with Space Medicine
„
Delivery implant
a Preprogrammable: Autonomy
a Remotely Activatable: Emergency; Tailoring
a Self-regulating: Autonomy; Emergency
a All three: Stability, Protection of Drug
Conclusions
„
„
„
„
Multiple nanotech platforms for molecular marker
harvesting/identification/profiling
Potential advantages: sample preprocessing,
multiplexing, quantitation, sensitivity, convenience,
speed, cost
Nanotech-based delivery systems: Injectable
nanovectors and nanochannel-based long-term
delivery implants
Key to both molecular diagnostic and multifunctional
therapeutics is multiscale mathematical modeling
(mmm), i.e. “Nano:mmm = drug:mechanism”
Conclusions/Space Medicine
„
Potential applicability/synergy:
a Biofluid Proteomics/Peptidomics for Early
Detection, Interventional Profiling and Monitoring
a Nanovector Therapeutics for Individualized,
Autonomous Interventions, Optimization of
Therapeutic Index
a Implant-based Therapeutics for Interventional
Autonomy, Management of Emergencies
„
Nanomedicine comprises multiple high- tech
platforms, ideally suited for NASA leadership
A Future Where No-one Suffers nor
Dies From Cancer
“A grand challenge is the ability to detect cancer
earlier – and the answer is almost certainly will
be nanotechnology”
“In addition to detecting cancer, nano-based
techniques will enable physicians to determine
whether a particular treatment is working”
Dr. Richard Smalley
Rice University
Nobel Laureate
1943-2005
Acknowledgments
„
„
„
„
„
Ohio State/Berkeley: Mark Cheng, Jay Tu, Xuewu Liu,
Sadhana Sharma, Wen-Hua Chu, Piyush Sinha, Jasper
Nijdam, Jason Sakamoto, Amy Pope-Harman
Former trainees (current faculty appointment): Tejal Desai
(UCSF/Berkeley), Miqin Zhang (Washington), Nicola Marzari
(MIT), Joe Nadeau (Duke), Luke Lee (Berkeley), Derek
Hansford and Jun Liu (OSU), Malisa Sarntinranont (Florida),
Mak Paranjape (Georgetown)
iMEDD: Carl Grove, Frank Martin, Rob Walzack, Peter
Dehlinger, Tony Boiarski, Kristie Melnik
Italy: Sabrina Pricl, Paolo Decuzzi, Carlo Cosentino, Enzo di
Fabrizio, Rosa Terracciano, Marco Gaspari, Gianni Cuda,
Salvatore Venuta
Lee Hartwell (FHCRC), Rick Smalley (Rice), Lance Liotta
(NCI), Vittorio Cristini (Univ. California Irvine), Chip Petricoin
(FDA), Peter Swaan (Univ. Maryland), Tuan-Vo Dinh (ORNL)
Antibody-Antigen Interactions
Cantilever with immobilized
Ricin antibodies undergoes
Bending
Response time can be
Reduced by using smaller
Liquid volume
700
600
500
400
300
200
40 parts-per-trillion sensitivity
100
0
-100
-10
0
10
20
30
40
50
Time (minutes)
(Thomas Thundat, ORNL)
Bending (nm) Vs Time of exposure to
Ricin
Detection of DNA hybridization
Probe
ssDNA
Target ssDNA
8240
8230
Frequency
8220
8210
8200
8190
8180
8170
-500
Wu, G. et al. “Origin of nanomechanical cantilever motion generated
from biomolecular interactions,” PNAS 98(4), 1560-1564 (2001).
0
500
Time
1000
1500
Global Cancer Mortality
14
12
Millions of people / year
10
Data Source: World Bank
TB
Malaria
HIV
Cancer
8
6
4
2
0
1990
2000
2010
2020
University of ‘Magna Græcia’ at Catanzaro – Italy
ROSA TERRACCIANO