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OUT LINE OF TALK
• Nano science, definitions, rationale and advantages of nano technology • Different nano materials and their possible applications in medicine. • Different types of nano technology available; Case studies and reviews. • Regulatory considerations for nano technology drugs • Nano business environment. • Nano technology products on the horizon • Closing thoughts
• Life sciences :- drug delivery, Lab-on- a –chip, drug design • Security :- molecular barcoding, chemical detection. • Materials :- powder, polymers • Electronics :- LCD, semi-conductors, memory • Energy :- Solar cells, fuel cells, membranes • Nano tools :- STM. AFMs
Definition :Nano particles are solid colloidal particles ranging in size from 10 nm to 1000nm (1 micron). They consist of macromolecular materials in which the active principle is dissolved, entrapped or encapsulated and/or to which the active principle is adsorbed or attached to and can be used for therapeutic disease management, silicon chip, biomedical applications etc..
The application of nano materials for medical diagnosis, treatment of failing organs or prevention and cure of human diseases is generally referred to as nano- medicine. Whereas the branch of nano- medicine devoted to the development of bio-degradable or non-bio dgradable prostheses falls within the purview of nano-biomedical science and engineering
Some terms in Nano-science include:• Nano structure :- 1 to 100 nm • Nano- crystals :- Crystalline solid with grain sizes 1to 100 nm • Nano coatings :- individual layers or multi-layer surface coating in the range 1 to 100 nm • Nano powders :- extremely fine powders with average particles size in range of 1 to 100 nm • Nano fibres :- fibers with a diameter in the range of 1 to 100 nm
Then why nano tech based drug products ?
Because of their combination of properties- including subcellular size and controlled release capability and susceptibility to external activation- devices/delievry systems produced using nano technology enable new applications in biological and medical science and focus on formulating therapeutics agents in bio-compatible nano composites such as nano particles, nano capsules, micellar systems and conjugates.
Not necessarily !!!!!
“Nanosizing” of Drugs
– – – – – – – – Deals with “Particle size reduction” of drugs . And leads to: Increase surface area Enhance solubility Increase rate of dissolution Increase oral bio-availability Produce rapid onset of therapeutic action Decrease the dose needed Decrease fed/fasted variability Decrease patient to patient variability
What is Nano technology?
• Research and technology development at the atomic or macromolecular levels, in the length scale of approximately 1-100 nm range…..by Creating and using structures, devices and systems that have novel properties and functions because of their small or intermediate size. …and has Ability to control or manipulate on the atomic scale…….offering Solutions to human health challenges in treating cancer, neurological and psychiatric disorders, vaccines, gene therapy and protein therapeutics.
Rationale and evolution of concept of nano technologyThe fact that most drugs have not only positive pharmacological effects , but they also exhibit side effects , makes the concept of drug targeting very attractive. This concept was visualised by Paul Ehrlich in 19th C where in he described a “ magic bullet” which guides a drug directly into its target cell and the drug will not affect surrounding cells.
Advantages of nano technology for drug therapy :1. 2. 3. 4. 5. Rapidly growing area of science Anticipated to lead to the development of NDDS. Private sector, academia and federal agencies spend more on this area of science. Permits solubilization of insoluble and chargeable drugs Long plasma circulation especially to achieve sustained release of drugs
Advantages of nano technology for drug therapy :.. Contd./6 - Passive targeting:- Nano particles provide targeted (cellular/tissue) delivery of drugs , to improve oral bioavailability, to sustain drug/gene effect in target tissue, to solubilize drugs for intravascular delivery and to improve the stability of therapeutic agents against enzymatic degradation, especially of proteins, peptides and nucleic acid drugs.
7- : Due to their subcellular and sub-micron size, nano particles can penetrate deep into tissues through fine capillaries, cross the fenestration present in the epithelial lining (e.g.liver) and are generally taken up efficiently by the cells. This allows efficient delivery of the therapeutic agents to target sites in the body.
8- By modulating polymer characteristics, one can control the release of
therapeutic agent from nano particles to achieve desired therapeutic level in target tissue for required duration for optimal therapeutic efficacy. 9- Nano particles can be delivered to distant target sites either by localized delivery using a catheter –based approach with a minimal invasive procedure or they can be conjugated to a bio-specific ligand which could direct them to the target tissue or organ.
PLATFORM TECHNOLOGY AVAILABLE
Four different types of nano-technology are available :
1. 2. 3. 4. Polymersomes :- eg. dendrimers Hydro gel matrices :- e.g. micelles, dendrimers- micelle combination Bio-degradable nano particles :- e.g. red blood cells, gelatin, PEG etc. Nano vesicles/ nano fiber mats : e.g. buckey balls, nano mats etc. 1-3 are normally used in delivery systems and 4 primarily used in implants.
Polymersomes have a significant advantage due to their stability, the ability to introduce multiple functions easily and to engineer the ideal micro- environmental for the molecule, while eliminating leakiness. For e.g., to achieve oral administration of proteins, insulin, vaccines (where mucosal response is desired) and other biologicals, this technology is being co-developed with hydrogel matrice technology
Nano vesicles and nanofiber mats are echogenic contrast agents, which are amenable to parenteral administration, offering the dual capability of drug delivery and tissue /cell targeting. The stabilized micro bubbles/ contrast agents when exposed to an ultrasonic beam at the imaged area, can be stimulated to release its contents , thereby delivering the drug to the visualized area.
Complex nucleic acids with modified spermines, which have been shown to result in cell specific targeting. The goal is to develop hepatocte and macrophage targeting complexes of DNA. The former is for gene therapy, while the latter serves to enable genetic vaccines to be efficacious.
Requirements of an ideal vector (or NANO MATERIAL ) for drug targeting are as follows:1. 2. 3. 4. 5. Carrier is capable of extended circulation in the bloodstream It must be small enough to gain access to target tissues and tarot cells. It must have flexible tropisms for applicability in a range of disease targets It must be able to deliver the active moiety into the cells and following endocytosis and It must be capable of escaping endosome –lysosome processing.
• • • Multifunctional materials that interact with biological systems in well controlled ways Exhibit unique properties and functions because of their small size. Include such structures as: – Carbon nanostructures – Dendrimers – Metal oxides (FeO, TiO2, ZnO) – Quantum dots (CdSe) – Some liposomes – Engineered gene circuits, Chitosan, PEG, PEG coated lactic acid, polyalkyl cyanoacrylate, polyglutaraldehyde, gelatin, solid lipid nanoparticales, silicon micro-chip
• Spherical polymeric molecules • Series of chemical shells built on a small core molecule (each shell is called a generation). • Made from a core and alternating layers of 2 monomers: acrylic acid and diamine. • Molecular structure has the form of a tree with many branches. • Can serve as nano-devices for delivery of therapeutics.
Applications of dendrimers in nano technology based drug product development
• Biologic nanodevices based on dendrimers are being developed with the potential to : – Recognize Cancer cells – Diagnose cause of cancer – Delivery of drug to target – Report location of tumor – Report outcome of therapy (cancer cell death) – (http://www.nano.med.umich.edu, James Baker, Univ. of Michigan)
The body distribution and elimination patterns of macromolecular systems are dictated mainly by their physicochemical properties , partile size, hydrophilicity and surface properties .After IV injection :• particles greater than 5-7 microns in diameter are cleared by capillary filtration mainly in lungs. • Particles with a diameter less than 5 microns are generally cleared from circulation by cells of the reticula- endothelial system (RES)
Bio degradable vesicles ….
Some examples of innovative Nano vesicle materials :• • • • • • Carbon nano strutures ( in implants ) Bucky balls ( in implants ) Nano tubes ( in implants ) Nano wires ( in implants ) Nano whiskers ( in implants ) Dendrimers ( delivery systems- implants combination products)
• Source of pure carbon (like graphite and diamond). • Based on fullerene molecules which are closed and convex cage molecules containing only hexagonal and pentagonal faces. • Examples of carbon nano structures: – Buckyballs – Nanotubes – Nanowires – Nanowhiskers
• Carbon nanotubes
– elongated fullerenes. – resemble graphite sheets wrapped into cylinders – Length to width ratio is very high (few nm in diameter and up to 1 mm in length)
– spherical fullerenes (C60 is most stable and symmetrical and resembles a soccer ball). – named after architect R. Buckminster Fuller . – 1996 Nobel prize in Chemistry awarded for their discovery.
Some Properties of Carbon Nanostructures
• High tensile strength • Physically stable • Chemically reactive with free radicals – Derivatives can be formed • More hydrophilic than fullerenes • New organic molecules can be generated • Other atoms can be placed inside its “cage” (doping with alkali metals) – Superconducting properties – Optical properties (endohedral fullerenes)
Several Nanocarbon Structures
Leading the Way…Drug-Eluting Stents
Drug-eluting stents “represent the pinnacle of the combination product field, which harnesses the strengths of the device industry and those of the drug or biologics industry to produce technologies that could not be developed by either sector alone.”
[Swain E. Blazing New Paths for Product Introductions. MDDI Sept/Oct 2003. Available on www.devicelink.com]
Regulatory Considerations for Nano technology Drugs include…….
• • • • Nomenclature Quality Safety Environmental Impact
Nanomaterials are not new to FDA
• Many approved products currently on the market with components manufactured in the nano scale range (drugs, sunscreens, cosmetics…). • Most drugs act at their site of action as individual molecules that are in the nano size range
– Critical attributes of nano technology products might include: • Particle size and size distribution • Surface area, surface chemistry, surface coating, porosity • Hydrophilicity, surface charge density • Purity, sterility • Stability (aggregation, protein adsorption) • Does in vitro behavior reflect in vivo behavior – Manufacturing and Controls – Drug release parameters and bio-equivalence testing considerations.
Preclinical Safety Assessment
• Current required studies for drug applications generally include: – In vivo short-term and long-term toxicity in rodent and non-rodent species, ADME, pharmacology, safety pharmacology, genotoxicity, developmental toxicity, irritation studies, immunotoxicology, carcinogenicity and other possible studies. – Additional studies might be requested based on drugspecific considerations.
Preclinical Safety Assessment (cont’d)
• Studies in In vitro models – Target binding/receptor screens – Cellular uptake – Cytotoxicity • Studies in In vivo models – Efficacy/proof of concept – Imaging studies – Special toxicology studies (functional studies?) – Mechanisms of tissue uptake and tissue clearance
• Depend on reported physical characteristics and biological effects of specific nanomaterials. • 1. Facility design considerations • Limiting cross contamination between different products manufactured in the same facility. • Limiting contamination by components of machinery used in the manufacturing process • 2. Impact of nanotechnology products on the environment • Disposal of unused/expired products. • Potential environmental impact of material entering the environment after administration.
NANO BUSINESS ENVIRONMENT
(Reviews on pharma products on horizons of commercialization developed on nano- particles- platform technology)
Nano tech- Product Examples
• Wound Care – dermal fibroblasts seeded on a 3-D bioabsorbable scaffold. For hard to heal wounds, e.g diabetic foot ulcers.
[Dermagraft, Advanced Tissue Sciences]
Nano tech- Product Examples…contd./..
• Orthopedics – titanium spinal fusion cage and absorbable collagen sponge with recombinant bone morphogenic protein (rhBMP-2). For lumbar fusion, degenerative disc disease. [InFUSE, Medtronic] Drug Delivery / Oncology – implanted polymer wafer with chemotherapeutic agent. For sustained-release drug delivery to treat malignant glioma. [Gliadel, Guilford Pharmaceuticals Inc.]
Nano tech- Products on the Horizon
• Light Infusion Technology - photosensitizer drugs activated by light-emitting diode devices for solid tumor destruction [Light Sciences Corp.]
• Bioartificial Pancreas – active Islet of Langerhans cells that sense and secrete insulin, and thin sheet of polymer seeded with living islets, implanted in peritoneal cavity.
[Islet Sheet Medical]
Nano tech Products on the Horizon…contd./• Controlled-release microchip drug delivery systems - “Pharmacyon-a-Chip”. Microfabricated silicon microchip, stores drugs in reservoirs covered by gold or polymer membrane. Automatically releases medications at programmed intervals. [research conducted at U. of Toronto, MIT, U. of Texas-Austin, Cornell U.] Cardiology applications – hybrid drug-device for cardiac arrhythmias – biologics to create a sinus atrial node, the heart’s natural pacemaker – cell therapy for heart muscle tissue regeneration
NANO BUSINESS ENVIRONMENT
Altair Technologies Inc. Bio Sante Pharmaceuticals FEI Co. Flamel Technologies , S.A. Harris & Harris group , Inc. JMAR Technologies, Inc. MFIC corporation Nanogen, Inc. Nanophase technologies corp. Nano-properietary Inc. NVE Corp. Pharmacopia, Inc. Skye Pharm PLC SYMYX technologies Veeco Instruments Inc. Nano material manufacturing Nano particlulate- based vaccine adjuvant and delivery system Nano- profilometry (SNP) imaging systems Bio-pharmaceutical drug delivery systems. Nanotech venture capital group Plasma lithography at sub-100nm level Fluid materials processing systems Nanochip molecular biology workstation Nanocrystalline materials Carbon nanotube technology Spintronics Drug discovery and chemical dvelopment process Integrated drug discovery Nanomaterial discovery Nanoman, PicoForce, Nanoscope
SELECTED NANOBIO-TECHNOLOGY COMPANIES DEVELOPING BIO-ANALYSIS APPLICATIONS Technology SPM Companies Hitachi High technologies (London) Image scientific Instruments (Madison) Veeco (Woodbury, NY) Affymetrix (Santa Clara) BioForce Nanosciences (Ames, IA) Nanogen (SanDiego) Nanolink (Chicago) Platforms Electron -beam lithography (on market) Leap-atom probe microscope (on market) Near-field scanning optical microscope (on market) High- density oligonucleotides (GeneChip) arrays (on market) Nanoarrays- 10,000 fold-smaller than conventional arrays (on market) Oligonucleotide arrays with polarised features ( on market) Dip-pen nanolithography system ( on market)
Dendritic nanotechnologies (Mt.Plesant, MI) Dendrimers ( on market) Evident Technologies 9 Ocean Optics USA) Semi conductor nanocrystal quantum dots ( on market) Genicon Sciencies ( SanDiego) 2 color microarray kit resonance light- scattering detection and imaging instrument Nano Plex ( Mountain View CA) Nanosphere (Chicago) Quantum Dot ( Haywood CA) Nano- bar codes particles kit ( on market) Gold- nanoparticle probes and detection systems Quantum-dot conjugates ( steptavicin, protein A, biotin- on market) Microfluidics ( Lab Chip- on market) Multi-layer soft lithography microfluidics High through put screening platforms High through-put screening platforms using soft lithography and biosurface chemistry
Caliper Technologies (MountainView CA) Fluidigm ( San Francisco) Nanostream (Pasadena CA) Surface Logix ( Brighton, MA)
S E L E C T E D N AN O-B IOT E C H N OL OGY C OMP AN IE S D E V E L OP IN G ME D IC AL D E V IC E S
Focus Com p a n y P la tfo rm un de r de ve op m e nt
Tis s ue engineering A ngs tronM edic a (Newton) NanoM ateria (Chic ago)
Nanos truc tured hy drox y apatile artific ial bone m atrix Nanos truc tured m aterial for heart, c artilage and nerve regeneration
pS iM edic a ( the M alverns , UK )ioS ilic on for bone im plants B B ioS ens ors A gilent )P alto CA ) Nanopore s equenc ing (in c ollaboration with Harvard univers ity )
454 Life S c ienc es ( B ranford,PCT) ic oTiter s equenc ing plate US G enom ic s (W oburn) nanom ix (E m ery ville, CA ) S ingle-s trand DNA s equenc ing Nanotube c hem ic al bios ens ors
Nano bio-technology companies developing drug delivery and therapeutic applications
Therapeutics Company Alinis BioSciences (Emeryville CA) ALZA ( MountainView, CA) Nanocrystal Technologies (King of Prussia, PA) NanoMed Pharmaceuticals (Kalamazoo, MI) Star - Pharma ( Melbourne) Platforms Polyfunctional nanoparticles Lipid nano particles with PEG coating doxorubicin liposomes-( on market) NanoMill technology for creating nanocrystals Nanotemplate engineering for drug and vaccine delivery systems VivaGel anti-HIV dendrimer (Phase-I)
Advectus Life Sciences (West Vancouver) Bio Delivery Sciences (Newark) BioSante Pharmaceuticals (Lincolnshire) C-Sixty ( Houston) Cytimmune Sciences ( College Park, MD) NanoCarrier (Chiba, Japan) NanoBio (Ann Arbor, MI) NanoSpectra BioSciences (Houston) Tageromes (Palo Alto, CA)
NanoCure systems for delivery of anti cancer drugs across blood- brain barrier. BioOral nanochelates cigar-shaped structurs comprised of lip bilayers Nanoparticulate platform (CAP) for drug delivery (Phase-I) Fullerene - based drug delivery Tumor necrosis factor bound to colloidal gold nanocrystal for targetting tumors, vectors with docking site for gene therapy. NanoCap micellar nanoparticle for water- insoluble drugs (under development) Anti-microbial nanoemulsions (Phase-I) Nanoshells for optical therapies Injectable nanospheres for therapeutic or diagnostic agents
• • • • • Very young field, will grow quickly Watch for new sources to cover this emerging industry No indexing specific to nano tech-combination products Non-standard terms used in science. Active work on nano- technology are focused in the domains of orthopedic, dental, bladder, neurologic, vascular, cartilage and cardiovascular applications.
• Incorporates many technologies – Biomaterials & Coatings – Genomics & Proteomics – Tissue Engineering – Micro- & Nano technology – Advanced drug delivery – ‘Traditional’ drugs & devices
• Focus on disease cure (drugs, biologics) rather than treatment (devices) • Ultimate disease cures will come from biotech, unless pharma industry co-opts it • Nano tech- products “cannibalize” existing products; replace drugs . Few large manufacturers have both drug and device components • Cross-industry partnerships and acquisitions • Disparate industries must work together
Future image of Nanoparticles
• Frost & Sullivan – Medical Device Technology Alert; Inside R&D; Advanced Manufacturing Technology; High-Tech Materials Alert; Advanced Coatings and Surface Technology • Espicom Publications – Drug Delivery Intelligence File; Cardiovascular Device Business; Drug Delivery Insight; Medical Industry Week thru- www.google.com
Information sources (cont.)
Web Sites • Medical Devicelink – www.devicelink.com • BIO – Biotechnology Industry Organization www.bio.org • SCIRUS – www.scirus.com • AdvaMed - www.advamed.org • MDMA (Medical Device Manufacturers Association) – www.medicaldevices.org • Society for Biomaterials - www.biomaterials.org • FDLI (Food & Drug Law Institute) www.fdli.org • AAMI (Association for the Advancement of Medical Instrumentation) – www.aami.org