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


Other title
polymeric micelles
polymeric vesicles
multi-drug resistance
block copolymer
Type of item
Degree grantor
University of Alberta
Author or creator
Binkhathlan, Ziyad
Supervisor and department
Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
Brocks, Dion R. (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Wasan, Kishor (Faculty of Pharmaceutical Sciences, University of British Columbia)
Unsworth, Larry D. (Department of Chemical and Materials Engineering)
Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Sciences)
Loebenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences)
Faculty of Pharmacy and Pharmaceutical Sciences

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
License granted by ZIYAD BINKHATHLAN ( on 2011-07-26T20:07:30Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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