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Protein Therapeutics_ Delivery.ppt

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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            Carbon                  Fulleren
Tube                   Nanohorn                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
                        Apolipoprotein E (apoE)
        Apolipoprotein
        Essential for the normal catabolism of
        triglyceride-rich lipoprotein constituents


        Chylomicrons
        Transport dietary lipids from the intestines to
        other locations in the body



            Deficiency related to familiar
            heart disease




                                                          34kD   PDB: 1B68
Wikipedia
                  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                     vs                   Graft
Pros:   Easily Manage Dosing                 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
                                             Cons: Invasive
        Suffer from Varied Absorption
                                                      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.

				
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