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Enhanced Intranasal Delivery of Gemcitabine to the Central Nervous System

Krishan, Mansi
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384850749

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Drug transport to the brain for the treatment of neurological diseases is a challenge due to impenetrable nature of the blood brain barrier (BBB). Intranasal (IN) drug administration is a non-invasive approach for rapid direct drug delivery from the nose to the central nervous system (CNS), thereby minimizing systemic exposure. The current study focuses on a strategy to enhance the delivery of the nucleoside drug gemcitabine (GEM) to the CNS via IN administration. Our approach took advantage of the fact that the BBB and olfactory epithelial tight junctions (TJs) share many proteins in common. We hypothesized that by transiently increasing the permeability of nasal epithelial tight junctions using the BBB permeabilizer papaverine (PV), we would increase the concentration of GEM reaching the brain extracellular fluid (BECF) following IN delivery, with the goal of delivering therapeutic concentrations of nucleoside drugs to the CNS. Experimental methods included IN administration of fluorescein isothiocyanate-dextran beads (FD4), GEM and PV, in-vitro GEM recovery, in-vivo brain microdialysis for BECF collection, HPLC analysis to measure GEM in BECF, histopathology, western blot analysis and immunofluorescence localization. Distribution studies with FD4 showed significant deposition in the ethmoid turbinates, suggesting drug uptake through olfactory epithelium. Clinically relevant doses of PV (up to 1.4% IN) did not cause histological evidence of cytotoxicity or inflammation in nasal epithelia, lung, liver, spleen, or kidney. Pharmacokinetics of GEM in BECF for PV (1.4%) + GEM (50mg/kg) treated animals showed almost four fold increase in area under the curve as compared to no PV treatment group. Western blot analysis suggested that IN PV treatment increased permeability through olfactory epithelial TJs by transiently decreasing the levels of TJ protein phospho- occludin. Immunofluorescence staining showed reversible alteration of occludin localization in olfactory epithelium following IN PV treatment. Thus, transient permeabilization of nasal epithelial TJs provides a non-invasive means to enhance delivery of nucleoside drugs to the CNS.
Mary Beth Genter, Ph.D. (Committee Chair)
Pankaj Desai, Ph.D. (Committee Member)
Gary Gudelsky, Ph.D. (Committee Member)
Marepalli Rao, Ph.D. (Committee Member)
Howard Shertzer, Ph.D. (Committee Member)
142 p.
Toxicology
Intranasal drug delivery; Nucleoside drug; Papaverine; Blood brain barrier; Paracellular transport; Brain extracellular fluid

Recommended Citations

Citations

  • Krishan, M. (2013). Enhanced Intranasal Delivery of Gemcitabine to the Central Nervous System [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384850749

    APA Style (7th edition)

  • Krishan, Mansi. Enhanced Intranasal Delivery of Gemcitabine to the Central Nervous System. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384850749.

    MLA Style (8th edition)

  • Krishan, Mansi. "Enhanced Intranasal Delivery of Gemcitabine to the Central Nervous System." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384850749

    Chicago Manual of Style (17th edition)

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© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.