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Transcript 
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.
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