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Nanomedicine _ Nanotherapeutic Devices


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									What We should Know About the
    Emerging Technology:

         Joseph F. Chiang
    Department of Chemistry and
       Oneonta, NY 13820
Technological developments for the
        Last half Century
Outline of developments:
1. In the middle of the 40’s, the most
    important invention: Transistors to
    semiconductors(Shockley, Bardeen,
    Braintain,, at Bell Laboratories).
    This led to the later development of
     integrated circuit(IC) and PC
2. In the early 60’s, laser(light amplification
    by stimulated emission of radiation).
    Everyone is benefited by this
   development- music, entertainment,
   healthcare, communication, etc.
3. In the early 70’s, Integrated circucit(IC)
    and Personal computer(PC) were
   developed( main frame computers, such
    as IBM 360, CDC 6600, UNIVAC 1108;
    Minicomputer-DEC, Gray, etc. were built
   before PC).
4. In the early 80’s, superconductors were
    revived. Many medical instruments were
    built, such as MRI(Magnetic Resonance
    Imaging). The term: NMR(Nuclear
    Magnetic Resonance) were avoided
    since the word: Nuclear.
    We all have some background on
    semiconductor, laser, superconductor,
    and IC/PC.
5. The most current development:
   Numerous applications in
   nanotechnology exist, such as in
   electronics, physics, chemistry,
   engineering, materials sciences.
My talk will concentrate on application in
medicine: Nanomedicine.

What is nanotechnology?
 To build matter from atoms/molecules, a
  bottom-up technique;
 All matters were built historically with top-
 down technique.
 Chemistry is a nanotechnology- combining
 atoms/molecules to build bulk materials.
Example of Bottom-up Approach:
 Proteins are synthesized from lower
 molecular weight amino acid precursors by
 chemically or biologically mediated
Top-Down Approach:
 Carbon Nanotubes can synthesized from
 graphite sheets in an electric arc oven
 by metal catalytic method.
All the above-mentioned materials are built
in nanometers. (1 nano meter = 10-9 meter).
  Protein        MW          Size_________
  Hemoglobin     68KDa      4.5x7nm

  Lipoprotein    130KDa     20 nm

  -globulin     90KDa      4.3x26 nm

  Fibrinogen     406KDa     4x76 nm
d=size parameter of fundamental,
  biological building block:
  d=.12(MW)1/3 (nm)
MW= molecular weight in unit of dalton.
Some representative nanoparticles:
 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
• Quantum dots: if all 3 dimensions reach
The following chart will give our audience
some idea of scales and nanoscales.
One can visualize the scale from tennis
ball, a period(.), and virus.
Medical Applications are shown as follows
Various molecules were developed as
nanodevices for nanotherapeutic
applications as shown below:
The difference between traditional drug
delivery and nanotherapeutic drug delivery:
Drug Delivery System Technologies:

 Oral Drug Delivery
 Injection Based Drug Delivery
 Transdermal Drug Delivery
 Bone Marrow Infusion
Organ System Specific Delivery:
a. Pulmonary Drug Delivery
b. Nasal Delivery to Central Nervous
c. Cardiovascular System(CV)
d. Gastro-Intestinal Track(GI)
e. Genito-Urinary Track(GU)
f. Ocular Drug Delivery
Control Release System:

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.Therapeutic Monoclonal Antibodies,
   2.Liposomes, 3.Macroparticles
   4.Modified Blood Cells,5.Nanoparticles,
   6.Viral Assisted Intracellular Gene
   Delivery, 7.Non-viral Intracellular Gene
      Goals of Nano-therapeutics
1. Ways to treat Disease
2. Implants:
  Requirements of Nano therapeutic

• Devices should be non-invasive
• Devices target therapeutics payloads to
  site of disease.
• Devices should maximize therapeutic
  benefit and minimize undesired side
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.
Development of two types of polymers- Micelle:
  hydrophobic end facing inward, and hydrophilic
  end facing outward ( Radoslav Aavic, McGill)
 Dimension: 20-45 nm.
Using fluorescent light to track the micelle’s
  journey and to discover the whereabouts of the
  tiny container which passes 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
     Nanoceramic drug delivery
1. Reducing toxicity to non-diseased cells,
2. Increasing drug efficiency,
3. Being able to target and to 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 17Y2O3-19Al2O3-
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(t =64.1 h).
One of the great promises of
 nanotechnology- to increase control of
 personal health.
Understanding of disease-open the door to
 therapy for treating disease.
 Nanotherapeutic is one of the
 nanotechnology applications in treating
• 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.
• 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
• Gene Therapy- with understanding of
  human genome, one can understand
  and correct genetic defect.
• Therapy is to correct a missing or defect
         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
( by Triton BioSystem with Army Research
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.
3. Physicians 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 ~49 oC.
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.)
 Nanotherapeutic Devices

1. Oncology:

 Existing therapies-surgical, resection,
 radiotherapy, and chemotherapy-
 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
  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.
3. Nanotherapeutics & Specific Host
    Immune Responses

4. Nanotherapeutic Vaccines

5. Antibody Response to
   Therapeutic Devices.
6. Special Device Applications:

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.
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.
Micro and Nanotechnology in Drug Delivery

 • Synthesis and Preparations of
   nanoporous inorganic & organic
 • Use of biomolecules for targeting,
   adhesion, and biointerfacing
 • Nanofabricated & micro patterned drug
   delivery device
 • Formation & fabrication of
   nanoparticulate system modified with
   natural biological ligands.
          Present Focuses of Therapeutic
                 Delivery System

    Patients & Physicians
•   Improve drug delivery and
•   Enhance drug stability
•   Increase compliance
•   Potential for local delivery-
    decrease site-effect
       How Can Micro and
      Nanotechnology Help?
  Micro and nanofabrication allow for:
 Control for shape
 Control for size
 Asymmetrical 3D design
Requirements for Development
of new Biomaterials for Medical
Understanding of cell and biology,
tissue engineering, drug delivery and
other medical processes are required
for development in microscale,
nanoscale and biomimetics(bio-
inorganic chemistry, a bio-inspired
  Nanoceramics development leads to
1. Production of new implantable surface
   modified- medical devices,
2. Increase bioactivity, tissue
   regeneration and engineering,
3. Help cancer treatment, drug and gene
4. Deliver oxygen to damaged tissues,
5. Imaging for minimal invasive surgery,
6. Treat bacterial and viral infections.
  Definition of Biomaterials

Biomaterials are a non-drug substance
suitable for inclusion in systems of
bodily tissue or organs. These materials
are capable of being in direct contact
with body fluid and tissues for prolonged
period without side effect.(50% of
biomaterials are used in orthopedic and
dental application).
Biomaterials and Bioceramics
Foreign materials such as biomaterials in
contact with a living body can not be 100%
compatible. But materials at nanoscale
react in many ways: bioinert, bioresorbale,
and bioactive.
Bioinert materials
 They can be accepted by body, but do not
 interact or react with the physiological
 environment, such as alumnia.
Bioresorble Materials
 They are surface-reactive and dissolve in
 physiological environment to be replaced
 by soft/hard tissue.
Bio-active Materials
  Reacting with tissue and forming
  chemical bonding. Hyroxyapatite is an
  (See reference: Hench, et al., Ann. NY
  Academy of Science, 523, 54, 1988.)
The Advantage of Improving
bioceramics in nanoscale:
• Maintaining the physical functions
• Providing more interactions with the host.
      Types of Applications
1. Bone Replacement:

  Nanotechnology can be applied to the
  production of bonelike synthetic
  nanopowder and coatings of
  hydroxyapatite[HAp, Ca10(PO4)6(OH)2].
  HAp has been used for orthopedic and
  dental nanocomposites. (Particle size:
  15-20 nm diameter by 40 nm thickness)
HAp- a bioactive nanocrystallline

General formula:

(Ca, Mg, Na)10(PO4, CO3)6(OH)2
2. Calcium Phosphate Coatings
Co-Cr and titanium-based alloys are used
for thin film HAp coatings by thermal spray,
pulsed laser deposition, sputtering,
electro-deposition, or sole get technique.
     3. Simulated Body Fluid
  Nanoscale coatings and surface-
  modification techniques can be applied to
  body-interactive materials- nanoceramics:
 Helping body-healing
 Promoting regeneration of tissue
 Restoring physiological function.
    4. Nano- and Macro ceramics for
• Purpose of drug delivery.
• Having drug at specific site.
• Reducing toxicity to non-diseased cell.
• Nanoceramic systems can increase drug
• It also can target and control drug release.
• Glass microsphere of 17Y2O3-19Y2O3-
  4Al2O3-64SiO2(mole %) has shown to
  be effective for radiotherapy of liver
• The non-radioactive 89Y can be
  activated by 90Y with half-life of 64.1
  hour (90Y is a -emitter isotope)
5. Bioengineering Applications

Microtechnology and nanotechnology can
  be used for fabrication of biodevices:
a. planar devices(biosensor, arrays, DNA
b. micro/nano biodevices(nanoscale,
   biosensor, large-scale, integrated
   bisensor, etc.)
c. artificial organs or tissues
d. microfluidic devices and biochips
    (lab on a chip).
e. Biomimetics engineering
    (biomimetic system).
f. guided drug delivery to bio-MEMS
    (bio-microelectromechanical system)
       6. Tissue Engineering
• Use of stem cells( type of cell having
  ability to reproduce for a long period)
  incorporated into bioceramics to give rise
  cells that can make up tissues and organs
  of body.
• The nanoscale cultured cell/bioceramic
   composites can be used to fill gap in bone
  Nanoceramics for Gene & Drug
Layered double hydroxides(LDHs)-
 Gene or drug delivery into biological
 cells-a gene or drug delivery carrier
Composition of LDHs:
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

The biomolecules stored in LDH’s can
  be released under acidic condition.
Preparation of Nanoparticles of LDHs
The particles
prepared in
nanoscale for
• The bottom-up approach can make
  materials from atomic to mesoscopic
  and macroscopic scales.
• Nanotechnology can have impact on
  nanophotonics, separation techniques,
  catalysis, thermal coatings, sensor,
  cosmetics,nanomedicine, ceramics, and
  polymer composite applications.

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