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Protein Therapeutics: Delivery Devin Hudson Delivery Methods Intravenously Subcutaneously Suppository Intranasally * Orally Transinfection* Liquid Filled Nanoparticles as a Drug Delivery Tool. Venkatesan, N., Yoshimitsu, J., Ito, Y., Shibata, N. Takada, K. (2005) Biomaterials. 26, 7154-7163. Barriers to Oral Bioavailability • Percent Bioavailability: BA% • Poor Membrane Permeability • Enzymatic Degradation • Past Attempts: liposomes, nanoparticles, micro-spheres, hydragels, mucoadhesives, micro-emulsions Concept Erythropoietin (EPO) Hormone: Produced in Kidneys Erythropoiesis 1BUY PDB: 1BUY Porous Absorbents Carbon Nano Tube Carbon Nanohorn Fulleren es Other Porous Substrates: Silicon Dioxide, Charcoal, bamboo charcoal Treatment Jejunum: large surface area Blood EPO measured via Jugular vein with ELISA Absorption Enhancers Formulation G: labrasol Porous Absorbents Formulation A: CNT Protease Inhibitors casein vs lactoferrin Formulation G: Casein Conclusion BA% = 11.5 Systemic Delivery of Secreated Protein by Grafts of Epidermal Keratinocyctes: Prospects for Keratinocyte Gene Therapy. Fenjves, E. S., Smith, J., Zaradic, S. and Lorne, B. T. (1994) Human Gene Therapy. 5, 1241-1248 Wikipedia.org Concept Transfect with recombinant apoE-HA1 (pSV2neo) ELISA: Two Tests Graft skin Wikipedia.org Keratinocyctes and Aythmic Mice Stable Long Term Grafts Effectively Transduced via retrovirus Secretory tissue Newborn Foreskin Immune- deficient No Rejection Response Xenografts Nude Mouse Wikipedia Fractionation – Ficoll 400 Non-fractionated: total Small: basal compartment rich Intermediate: poorly characterized Large: terminally differentiated suprabasal cells Basal compartment keratinocyctes excrete endogenous apoE Mature Differentiated keratinocyctes do not excrete endogenous apoE Recomibant apoE expressed by any transfected keratinocytes Long Term Success Blood Serum apoE after 28 days Previous work: Viral promoters shut off over time Conclusion Higher Recombinant Expression in vivo Expansion in suprabasal cells in grafts Estimated that graft covering 2% of human skin could provide 6.5-8.9mg of recombinant protein per day. Oral Pros: Easily Manage Dosing vs Graft Pros: Doesn’t Require On-Going Care Quit/Start/Change Treatment Lower Long Term Expense Minimally Invasive Less Margin for Patient Error Lower Short Term Expense Less Risky than Systemic Transfection Cons: Require On-going Care Suffer from Varied Absorption Cons: Invasive Treatment Can Not be Stopped Easily Refrences Skin Patch Fenjves, E. S., Smith, J., Zaradic, S. and Lorne, B. T. (1994) Systemic Delivery of Secreated Protein by Grafts of Epidermal Keratinocyctes: Prospects for Keratinocyte Gene Therapy. Human Gene Therapy. 5, 1241-1248. Review Paper Leader, B., Baca, Q, J,. and Golan, D, E. (2008) Protein therapeutics: a summary and pharmacological classification. Nature Publishing Group. 7, 21-39. Oral Venkatesan, N., Yoshimitsu, J., Ito, Y., Shibata, N. Takada, K. (2005) Liquid filled nanoparticles as a drug delivery tool. Biomaterials. 26, 7154-7163.