Transcript Micro- and NanoTherapeutics Joseph F Chiang Department of Chemistry and Biochemistry State University of New York College at Oneonta Nanotechnology and Applications October 16, 2004

Micro- and NanoTherapeutics
Joseph F Chiang
Department of Chemistry and
Biochemistry
State University of New York College
at Oneonta
Nanotechnology and Applications
October 16, 2004
Micro- and Nano-Therapeutics
Nanotechnology –to build matter
from atoms/molecules-bottom-up
technique.
All matters were built historically
with top-down technique.
Chemistry is a nanotechnologycombines atom/molecules to build
bulk materials.
Characteristics of Common Routes of Drug
Administration
Quantum Wells, Wire and Dots
 Quantum wells: if one dimension is
reduced to nanoscale while the other
two remain large.
 Quantum wires: if 2 dimensions
reduced to nanoscale while the third
one remains large.
 Quantum dots: if all 3 dimensions
reach nanoscale
Approximate Sizes and Molecular
Weight of several Proteins
d=size parameter of fundamental,
biological building block:
d=.12(MW)1/3 (nm)
MW= molecular weight in unit of
dalton.
Protein
MW
Size
Hemoglobin 68KDa
4.5x7nm
Lipoprotein
130KDa
20 nm
-globulin
90KDa
4.3x26 nm
Fibrinogen
406KDa
4x76 nm
_________
Polypeptide nanowire:
In a manner,
amino acids
combine
together in
chain by
formation of
peptide bond.
DNA double nanowire:
Basic building block of
DNA is nucleotide, it is
a five member ring
deoxyribose with
phosphate group, a
nucleic acid base R.
Drug Delivery System Technologies
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Oral Drug Delivery
Injection Based Drug Delivery
Transdermal Drug Delivery
Bone Marrow Infusion
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Organ System Specific Drug
Delivery:
a. Pulmonary Drug Delivery
b. Nasal Delivery to Central
Nervous System(CNS)
c. Cardiovascular System(CV)
d. Gastro-Intestinal tract(GI)
e. Genito-Urinary Tract(GU)
f. Ocular Drug Delivery
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Control Release Systems
Novel Packaging and Formulations:
a. Fast Dissolving Tablets
b. Chewable Tablets
c. Solubility Enhancement

Targeted Drug Delivery:
a. Polymer and Collagen System
b. Particle-based system
1. Therapeutical Monoclonal
antibodies
2. Liposomes
3. Microparticles
•
4. Modified Blood Cells
5. Nanoparticles
6. Viral Assisted Intracellular Gene
delivery
7. Non-Viral Intracellular Gene
delivery
Implant Drug Delivery System
Goals of Nano-therapeutics
1. Ways to treat Disease
2. Implants:
Requirements of Nano therapeutic
Applications
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Devices should be non-invasive
Devices target therapeutics
payloads to site of disease.
Devices should maximize
therapeutic benefit and minimize
undesired side effect
Characteristics of Therapeutic
Nanodevices:
1. Biological molecule must retain
functions.
2. Device function is the result of the
activities of device component.
3. The relative organization of device
component drives device function.
4. Device function can be
unprecedented in the biological
world.
Characteristics of Nanobiological
Device
1. Minimally invasive
2. Target sites of disease
3. Sense disease states in order to:
- report conditions at the disease site to
clinicians;
- administer metered therapeutic
interventions.
4. Therapeutic function should be
segregated into standard modules
5. Modules should be interchangeable to
tune therapeutic functions.
Bionanotechnology
Applications for design and construct
materials at nanoscale in
biotechnology field.
Bionanotechnology-from natural
enzyme to manipulate genetic code
in order to modify organisms.
Biomaterials –result of application of
bionanotechnology.
Biomachines- to design molecular
machines at nanoscale, for example,
study of cancer cells.
There are hundred-thousand different
nanomachines inside human body.
Purpose of Nano-therapeutics
Discussions
Focused on nanodevices rather than
nanomaterials.
Purpose- serves as integral component
of drug delivery or other clinical
devices.
Incorporating biological structure into
nanobiological devices: special
challenge with traditional engineering
design
Nanocontainers
To deliver drug directly to cells.
(The effective drug treatment is
getting the medication to exactly the
right spot)
Research report in “Science”:
Methods to develop tiny containers of
nanocomposites to distribute drugs to
specific spot within individual cells.
Radoslav Aavic at McGill has developed
two types of polymers- Micelle:
Hydrophobic end facing inward,
Hydrophilic end facing outward
Dimension: 20-45 nm.
Using fluorescent light to tack the
micelle’s journey and discovered the
tiny container could pass through the
wall of a rat cell, but did not enter the
cell’s nucleus. It also did not penetrate
other part of the cell, as mitochondria.
Nanoceramic drug delivery
system
1. Reducing toxicity to non-diseased
cells
2. Increasing drug efficiency
3. Being able to target and control
drug release with high precision
(Several anti-cancer drugs fail in
their desired clinical activity due to
lack of specific target delivery.)
An Example:
Glass microsphere of 17Y2O3-19Al2O364SiO2(mol %) composition, 20-30
m diameter-effective for targeted
radiotherapy of liver cancer( 89Y is
non-radioactive, can be activated by
neutron bombardment to 90Y, a emitter(t½=64.1 h)
Nanomedicine
One of the great promises of
nanotechnology- to increase control
of our personal health.
Understanding of disease-open the
door to therapy for treating disease.
Nanotherapeutic is one the
nanotechnology applications in
treating disease.
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Nanotherapeutic devices are
created to find the target and to
correct it.
Immunotoxins-one component
binds to target cells, the other
component is the poison that kills
the cell.
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Liposomes-artificial membranes,
under specific conditions forming
small, closed vesicles composed of
a lipid bilayer that encloses a small
droplet of water.
Liposome size-20 nm-10m to
deliver drug.
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Gene Therapy- with understanding
of human genome, one can
understand and correct genetic
defect.
Therapy is to correct a missing or
defect protein.
Current Applications
Injection of the spheres into a
diseased liver through the hepatic
artery where they are entrapped in
small blood vessels to block blood
supply to cancer cells and
irradiating β ray to cancerous cells.
An Example:
The development of Targeted Nano
Therapeutics(TNT):
( by Triton BioSystem with Army
Research Lab)
(Continue)
The TNT system attacks cancer in 3
steps.
1. The patient receives a simple
infusion containing trillions of
bioprobes, each of which is a
nanoscale magnetic sphere bound
to an antibody,
2. The bioprobes will seek and attach
to cancer cells in the bloodstream,
(Continued)
3. The physician will switch on the
magnetic field in the region of the
cancer. This will cause the bioprobes
to heat up to kill the cancer cells
within minutes.
Another example:
A tumor or cancerous cell can be destroyed
at 43oC. Normal cells can be kept alive at
~49oC.
When ferri- or ferro-magnetite materials are
implanted, heating at alternating magnetic
field can kill the cancerous cells. If the
pore of the magnetic materials is
decreased to nanoscale, cancer cells can
be destroyed.
Use of ferromagnetic glass ceramic
containing 36 wt% of
magentite(Fe3O4), 200nm
diameter in CaO-SiO2 matrix.
The cancerous cells in the canal of
rabbit tibia were destroyed when
the device is inserted into tibia
and placed under an alternating
magnetic field of 300 Oe at 100
KHz.(Kokubo, et al.)
1. Nanotherapeutic Device in Oncology
Existing therepies-surgical, resection,
radiotherapy, and chemotherapyunfavorable.
Nanotherapeutic devices can be specifically
delivered to tumor by virtue of the size,
Therapeutic devices with cytoxins can not
leave the normal cells, but can leak to
tumor cells.
2. Cardiovascular Application of
Nanotherepeutics:
Current tissue engineering
approaches involve synthesis of 3-D,
porous scaffolds that allow,
adhesion, growth, and proliferation
of seeded cells to generate functional
vessel.
MEMS technology and nanoscale
control of molecular events
&interaction has been applied to the
development of cardiovascular
3. Nanotherapeutics & Specific Host
Immune Responses
4. Nanotherapeutic Vaccines
5. Antibody Response to
Therapeutic Devices.
6. Special Device Application.
a. Biosensors detect glucose level
for management of Diabetes:
Implanted sensors and noninvasive sensors are
underdevelopment to monitor
glucose level with glucose oxidase
which combine glucose and O2 to
form gluconic acid and H2O2. Pt
electrode is used to measure H2O2
level.
b. A biosensor using hemolysin to
detect short strand of DNA.
Hemolysin is embedded in a
membrane separating 2 chambers
which draws ions from one to
another. When nanopores are
blocked, an abrupt change in
current is detected(Chamber
dimensions: one with 3-4 nm in
diameter and the other with 1.4
nm in diameter).
c. Antibodies used as a biosensor
for blood type tester-composed of
a collection of antibodies that
recognize specific sugars on the
surface of red blood cells. The
antibody is added to the blood,
and if the particular blood type is
present in the cells, the antibody is
bind to the surface, sticky cells
together. The result is that a
clumping of cells can be detected
by human eye.
Soft Lithography
Synthesis of Poly (amido) amine
(PAMAM) (Bottom-Up Approach)
Top-down Approach:
Carbon nanotubes can be
synthesized with a top-down
approach from graphite
sheets in an electric arc oven by
metal catalyzed polymerization
method.
Bottom-up Approach:
Proteins are synthesized from lower
molecular weight amino acid
precursors by chemically or
biologically mediated
Polymerization.
Micro and Nanotechnology in Drug Delivery
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Synthesis and Preparations of
nanoporous inorganic & organic
platforms
Use of biomolecules for targeting,
adhesion, and biointerfacing
Nanofabricated & micropatterned
drug delivery device
Formation & fabrication of
nanoparticulate system modified
with natural biological ligands.
Present Focuses of Therapeutic
Delivery System
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Patients & Physicians
Improve drug delivery
and efficacy
Enhance drug stability
Increase compliance
Potential for local
delivery-decrease siteeffect
How Can Micro and
Nanotechnology Help?
Micro and nanofabrication allow for:
 Control for shape
 Control for size
 Asymmetrical 3D design
Oral Drug Delivery
The Current Drug Delivery
System Market Size:
$50 billions for 2003,
$67 billions for 2006( projected to
grow)
The total pharmaceutical market is
$250 billions in 2001.
Nanotech Medicine
NCI has launched a five-year initiative to
enlist nanotechnolgy to fight cancer.
$144 millions for the next five years to
support the initiative.
$90 millions will go toward funding several
Centers of Cancer Nanotechnlogy
Excellence.
$38 millions for targeted research grant in
the nanotech to fight against cancer
$16 millions set aside to train scientists to
work in this multidisciplinary environment.
Nanoceramics for Gene & Drug
Delivery
Layered double hydroxides(LDHs)Gene or drug delivery into biological
cells-a gene or drug delivery carrier
Composition of LDHs:
M(II)1-xM(III)x(OH)2(An-)x/nyH2O,
Where M(II)-divalent cation
M(III)-trivalent cation,
A =interlayer anion,
n-=charge on the interlayer ion.
(Inorganic or organic anions can be
introduced between hydroxide layer
by ion exchange or precipitation.)
Bio-LDH Nanohybrids
Biofunctional molecules- nucleoside
monophosphates, ATP, DNA,
flourescein-5-isothiocyanate, etc can
be intercalated into hydroxide layer
To form bio-LDH nanohybrids
Controlled Release of Interlayer
Biomolecules:
The miomolecules stored in LDH’s
can be released under acidic condition.
Preparation of Nanoparticles of LDHs
The particles
prepared in
nanoscale for
Intravenous
injection.
Number of Issued and Pending Patents and Number of
papers relating to Nanotube Applications
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Topics
Issued
Pending
Papers
Production
59
92
1189
Field-emission-related
devices
30
58
394
Electronics
11
27
360
Composites, fibers
7
36
111
Sensors, probes,detectors
7
23
129
Hydrogen storage, fuel cells 4
2
63
Batteries, capacitors
4
3
3
Other
30
33
3776
___________________________________________________________
Total
152
274
6026
Identity Badge under skin
FDA has approved “VeriChips”
manufactured by Applied Digital
Solution (Delray, Florida) to market
implantable microchips under skin.
An under-the–skin ID to access
medical information.