What We should Know About the Emerging Technology: Nanotechnology Joseph F. Chiang Department of Chemistry and Biochemistry SUNY-Oneonta 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, et.al., 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: Nanotechnology. 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 polymerization. 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 large. • Quantum dots: if all 3 dimensions reach nanoscale 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 (Continued) Organ System Specific Delivery: a. Pulmonary Drug Delivery b. Nasal Delivery to Central Nervous System(CNS) 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 (Continued) 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 delivery. Goals of Nano-therapeutics 1. Ways to treat Disease 2. Implants: 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 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. (Continued) 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 mitochondria Nanoceramic drug delivery system 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). ½ Nanomedicine 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 disease. • 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-10m to deliver drug. • 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. 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- 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. 2. Cardiovascular Application of Nanotherapeutics: 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 platforms • 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 efficacy • 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 Applications 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 fabrication). 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 delivery, 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 example. (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 nanoceramics. 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 Radiotherapy • Purpose of drug delivery. • Having drug at specific site. • Reducing toxicity to non-diseased cell. • Nanoceramic systems can increase drug efficiency. • 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 cancer. • 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 chips. 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 shaft. 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/nyH2O, 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 biomolecules stored in LDH’s can be released under acidic condition. Preparation of Nanoparticles of LDHs The particles prepared in nanoscale for Intravenous injection. Conclusion • 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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