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
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.
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 • Oral Drug Delivery • Injection Based Drug Delivery • Transdermal Drug Delivery • Bone Marrow Infusion
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
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
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
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-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
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 17Y2O3-19Al2O3-64SiO2(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(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.
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. 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 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 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.
3. Nanotherapeutics & SpecificHost 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 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.
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 • 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 • 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