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Development of block copolymer based nanocarriers for the solubilization and delivery of valspodar

  • Author / Creator
    Binkhathlan, Ziyad
  • One of the major causes of failure in cancer chemotherapy is multidrug resistance (MDR), where cancer cells become resistant to different types of anticancer drugs. Over-expression of membrane efflux pumps like P-glycoprotein (P-gp), which recognizes different chemotherapeutic agents and transports them out of the cell play a major role in MDR. One of the major reasons for shortcomings of P-gp inhibitors in clinic is their non-selective distribution to nontarget organs, which leads to reduced elimination of P-gp substrates (e.g. anticancer drugs) and intolerable toxicities by anticancer drugs. The objective of this research is to develop a nanocarrier that permits a change in the pharmacokinetics of P-gp inhibitors, limiting their non-specific distribution. Polymeric micelles have shown promise in changing the pharmacokinetics of hydrophobic drugs in a favorable manner. Presented herein are the results of our investigation of self-associating poly(ethylene oxide)-block-poly(ε-caprolactone)(PEO-b-PCL) and PEO-b-poly(α-benzyl-ε-caprolactone) (PEO-b-PBCL) block copolymers as biodegradable polymeric nanocarriers for the solubilization and delivery a model P-gp inhibitor valspodar). It is hypothesized that encapsulation of valsopdar in polymeric nanocarriers can enhance its therapeutic efficacy by providing an inert alternative to Cremophor EL for solubilizing valspodar, favorably changing its pharmacokinetics and reducing its pharmcokinetic interaction with anticancer drugs (P-gp substrates) upon co-administration. PEO-b-PCL and PEO-b-PBCL were assembled to form carriers of 60-100 nm diameters, and were shown to be able to efficiently encapsulate valspodar: achieving a clinically relevant aqueous solubility of 2.8 mg/mL. Following intravenous administration of valspodar to healthy rats, there was nearly a 100% increase in plasma area under the curve (AUC) of valspodar when administered in the polymeric nanocarrier formulations as compared to when Cremophor EL formulation was used. Co-administration of doxorubicin, a model P-gp substrate anticancer agent, with valspodar in the standard Cremophor EL/ethanol formulation resulted in more than 50% reduction in doxorubicin clearance, which was accompanied by over a 100% increase in doxorubicin AUC. In contrast, no change was detected in doxorubicin clearance or AUC, when valspodar was administered in PEO-b-PCL polymeric nanocarrier formulation. Overall, our results suggest that PEO-b-PCL micelles hold great promise for solubilization of valspodar and the safe co-administration with doxorubicin.

  • Subjects / Keywords
  • Graduation date
    2011-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R35T2F
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Brocks, Dion R. (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Unsworth, Larry D. (Department of Chemical and Materials Engineering)
    • Wasan, Kishor (Faculty of Pharmaceutical Sciences, University of British Columbia)
    • Loebenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences)