The Road Toward Precision Medicine Case Studies Shaker A Mousa PhD MBA FACC FACB FNAI Professor of Pharmacology Executive Vice President and Chairman of The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences ID: 1036368
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1. Impact of Nanobiotechnology on the Future of Medicine (Nanomedicine): The Road Toward Precision Medicine /Case StudiesShaker A. Mousa, PhD, MBA, FACC, FACB, FNAIProfessor of Pharmacology, Executive Vice President, and Chairman of The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences
2. Goal: From Nanomedicine to Precision Medicine“Personalized Nanomedicine”Precision Medicine
3. Nano” From the Greek word for “dwarf” and means for 10-9, or one billionth. In this case it refers to 10-9 meters, or 1 nanometer (nm).1 nm is about 3 atoms long.
4. Nano Synthesis, Design, Assembly and CharacteristicsBottom Up or Top Down
5. Could Enabling Technologies (Nanobiotechnology) Accelerate and Improve DDD ?Existing Drugs:1- Reformulation for Improved PK PD, and Safety: (Oral Insulin, Oral Proteins, Combination of multiple RX).2- Active Targeted Delivery: Improved PG, PK, PD, and Safety(Chemotherapy, anti-microbial, anti-Viral, Dyslipidemia,..)New Drugs:1- Formulation for Improved PK, PD, and Safety:Vaccine, gene therapy, others2- Active Targeted Delivery: (Intra-cellular versus extra-cellular)Improved PG, PK, PD, and Safety3- Bioimaging: (Early Detection/ Monitoring)
6. Case StudiesNanomedicine in Drug Discovery and Development (Shorten time, Mitigate Risk, Extend Product Life Cycle)I) Reformulation for Improved PK and PD (Nutraceuticals, Pharmaceuticals, and biopharma) II) Devices for rapid and sustained DeliveryIII) Nano-Targeted Drug Delivery for Improve Efficacy and Safety (Chemotherapy, Anti-microbial and Anti-viral, Dyslipidemia)IV) Nanomedicine and Blood Brain Barrier – GBM, and Neuro deliveryV) Bioimaging (Functional Imaging)
7. Classes of Active Pharmaceuticals (API) and impact of Pharmaceutical Nanosystems(Based on Solubility and Permeability)Drug Classes II and IVSolubility IIIIIIIVHighLowPermeabilityHighLowCorrelation between the degree of solubility and permeability for the 4 Classes of Drugs - Class I and III have favorable solubility in contrast to Classes II and IV.In term of Permeability Class I and II have favorable permeability in contrast to classes III and IV Passive vs. Active Targeting
8. Reformulation of Wyeth’s Rapamune® Improved BA + Improved ComplianceNanoparticulate SuspensionImproved oral BA by 27%Enabled preparation of tablet Enhanced patient convenience and acceptabilityImproved patient choiceProvided patent protection(Product Life Cycle)
9. Emend® (Aprepitant) Capsules (Based on Nanoparticulate Suspension) – Substance P Antagonist Improved oral bioavailability Reduced fed/fasted variability in bioavailability
10. Marketed Nanoparticulate Suspension ProductsRapamune® by Wyeth in 2001; Oral TabletProvides a stable tablet formulation (replaced a liquid dosage form) with 23% improvement in bioavailabilityEasier storage—no refrigeration requiredMore precise dosage/dosage linearityEMEND® by Merck in 2003; Oral CapsuleElimination of food requirement for drug (drug would otherwise have been abandoned) with 600% improvement in bioavailabilityTriCor® 145 by Fournier & Abbott, 2004; Oral TabletLower dose with 9% improvement in bioavailabilityMinimized food effectPatented formulationMegace® ES by Par, 2005 ; Oral SuspensionEquivalent efficacy achieved with lower absolute dosage with 28% improvement in bioavailabilityEasier administrationLower API costINVEGA® SUSTENNA® long-acting IM by Janssen, 2009 1 month Intramuscular dosage formEase of administration & potential higher patient complianceLiversidge E&G, ADDR, 2011, pg427Efficacy/Safety PKBasis of Filing√√√√√√
11. Robust, durable immunity by vaccination with single dose adjuvant-free HBsAg Chitosan NanoparticlesRobust serum anti-HBs titers in mice immunized with nanoparticle-encapsulated HBsAg. BALB/c mice were immunized i.p. with a single injection of 1.5 g of soluble free HBsAg (), nanoparticle-encapsulated HBsAg (), or HBsAg alum (). Weekly serum samples were analyzed for anti-HBs levels by ELISA. *p<0.05 2-way ANOVA. Mousa et al: Nanomedicine. 2013 Oct;9(7):923-34.
12. Case StudiesNanomedicine and Drug Discovery and Development (Shorten time, Mitigate Risk, Extend Product Life Cycle)I) Reformulation for Improved PK and PD (Nutraceuticals, Pharmaceuticals, and biopharma) II) Devices for rapid and sustained DeliveryIII) Nano-Active Targeted Drug Delivery for Improve Efficacy and Safety (Chemotherapy, Anti-microbial and Anti-viral, Dyslipidemia)IV) Nanomedicine and Blood Brain Barrier – GBM, and Neuro deliveryV) Bioimaging (Functional Imaging)
13. TaxolAbraxane (nab-paclitaxel) is a solvent-free ‘nano’ version of Taxol (cremophor-based paclitaxel) – Passive TargetingContents:Paclitaxel 6 mg/mlCremophor 537 mg/mlEthanol 396 mg/mlContents:100 mg paclitaxel900 mg albuminNo Surfactants/SolventsAbraxane received FDA Approval 2005 for metastatic breast cancerNOW IT IS EXPANDED TO VARIOUS TYPES OF CANCERAbraxane
14. Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res. 2004 Jun 11;94(11):1500-6.Thyrointegrin avb3 Receptors
15. Active Targeting Modalities [ Small Molecules, Antibody, Aptamer, and others]Example Thyrointegrin avb3 receptors are generously expressed by tumor cells and rapidly-dividing blood vessel cells, enabling us to target these cell populations with Nano-Propyl Diamino tetrac to deliver chemotherapies (Cisplatin, Paclitaxel).Nanomedicine (Lond) 2013 Dec;8(12):1943-54.Angiogenesis. 2014 Jul;17(3):463-9.
16. ** P < 0.05 Vs. Cisplatin, **P <0.0001 Vs. Cisplatin or Nano-cisplatin**
17. Paclitaxel uptake in pancreatic (SUIT-2) tumors After 3 weeks of treatment with paclitaxel, Nano-paclitaxel or Nano-Diamino-tetrac-paclitaxel****P <0.001 versus paclitaxel or NanopaclitaxelInt. J Nanomedicine. 2017;12:1305-131510 folds greater delivery with NDAT-Paclitaxel versus 2 folds with Nab-Paclitaxel (Abraxane)
18. Era of Personalized Medicines!
19. The Growth of Nanotechnology and its applications is on the rise2030
20. Nanomedicine and Future AdvancesMulti-functional Diagnostic Imaging and Therapeutic: Matching a Tumor To a Drug (Personalize)Improve Efficacy and Safety of Existing and New DrugsTargeting the Immune System at tumor/micro-environmentVaccine and Gene TherapyBiosensor and Auto-Medicine Delivery Biocompatible Implants and body parts (Tissue Engineering and Regeneration)“Increased Compliance, Improved Disease classifications, Curative therapy and Improved Quality of Life”