Micro and Nano Therapeutics

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

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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 nanotechnology- combines
  atom/molecules to build bulk materials.

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Characteristics of Common Routes of Drug
Administration
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• 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

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Approximate Sizes and Molecular Weight of several
Proteins

• dsize parameter of fundamental,
• biological building block
• d.12(MW)1/3 (nm)
• MW molecular weight in unit of dalton.

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• Protein MW Size _________
  Hemoglobin 68KDa 4.5x7nm
• Lipoprotein 130KDa 20 nm
• ?-globulin 90KDa 4.3x26 nm
• Fibrinogen 406KDa 4x76 nm

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• Polypeptide nanowire
• In a manner,
• amino acids
• combine
• together in
• chain by
• formation of
• peptide bond.

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• 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.

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Drug Delivery System Technologies

• 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

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• Targeted Drug Delivery
• a. Polymer and Collagen System
• b. Particle-based system
• 1. Therapeutical Monoclonal
• antibodies
• 2. Liposomes
• 3. Microparticles

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• 4. Modified Blood Cells
• 5. Nanoparticles
• 6. Viral Assisted Intracellular Gene
• delivery
• 7. Non-Viral Intracellular Gene
• delivery
• Implant Drug Delivery System

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Goals of Nano-therapeutics

• 1. Ways to treat Disease

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2. Implants
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Requirements of Nano therapeutic Applications

• Devices should be non-invasive
• Devices target therapeutics payloads to site of
  disease.
• Devices should maximize therapeutic benefit and
  minimize undesired side effect

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• 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.

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• 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.

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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.

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• Biomachines- to design molecular machines at
  nanoscale, for example, study of cancer cells.
• There are hundred-thousand different
• nanomachines inside human body.

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Purpose of Nano-therapeuticsDiscussions

• 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

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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.

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• 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 micelles
  journey and discovered the tiny container could
  pass through the wall of a rat cell, but did not
  enter the cells nucleus. It also did not
  penetrate other part of the cell, as
  mitochondria.

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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.)

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• An Example
• Glass microsphere of 17Y2O3-19Al2O3-64SiO2(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(t½64.1 h)

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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.

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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 ß ray to cancerous cells.

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An Example

• The development of Targeted Nano
  Therapeutics(TNT)
• ( by Triton BioSystem with Army Research Lab)

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• 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,

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• 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.

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• 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.

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• 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.)

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1. Nanotherapeutic Device in Oncology

• Existing therepies-surgical, resection,
• radiotherapy, and chemotherapy-
• unfavorable.
• 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.

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• 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 sensors.

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• 3. Nanotherapeutics Specific Host Immune
  Responses
• 4. Nanotherapeutic Vaccines
• 5. Antibody Response to
• Therapeutic Devices.
• 6. Special Device Application.

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• a. Biosensors detect glucose level for management
  of Diabetes
• Implanted sensors and non-invasive 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.

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• 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).

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• 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.

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Soft Lithography
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Synthesis of Poly (amido) amine (PAMAM)
(Bottom-Up Approach)
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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.

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Bottom-up Approach

• Proteins are synthesized from lower
• molecular weight amino acid precursors by
  chemically or biologically mediated
• Polymerization.

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Micro and Nanotechnology in Drug Delivery

• 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.

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Present Focuses of Therapeutic Delivery System

• Patients Physicians
• Improve drug delivery and efficacy
• Enhance drug stability
• Increase compliance
• Potential for local delivery-decrease site-effect

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How Can Micro and Nanotechnology Help?

• Micro and nanofabrication allow for
• ? Control for shape
• ? Control for size
• ? Asymmetrical 3D design

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Oral Drug Delivery
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• 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.

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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.

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Nanoceramics for Gene Drug Delivery

• Layered double hydroxides(LDHs)-
• Gene or drug delivery into biological
• cells-a gene or drug delivery carrier

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• 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.)

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Bio-LDH Nanohybrids

• Biofunctional molecules- nucleoside
• monophosphates, ATP, DNA,
• flourescein-5-isothiocyanate, etc can
• be intercalated into hydroxide layer
• To form bio-LDH nanohybrids

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• Controlled Release of Interlayer
• Biomolecules
• The miomolecules stored in LDHs
• can be released under acidic condition.

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Preparation of Nanoparticles of LDHs

• The particles
• prepared in
• nanoscale for
• Intravenous
• injection.

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• Number of Issued and Pending Patents and Number
  of papers relating to Nanotube Applications
• ____________________________________________
• 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

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Identity Badge under skin

• FDA has approved VeriChips manufactured by
  Applied Digital Solution (Delray, Florida) to
  market implantable microchips under skin.
• An under-theskin ID to access medical
  information.