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valspodar, cancer, pharmacokinetics, P-glycoprotein, polymeric micelles, polymeric vesicles, multi-drug resistance, block copolymer

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

Department: Faculty of Pharmacy and Pharmaceutical Sciences

Specialization:

Date accepted: 2011-07-27T14:02:33Z

Graduation date: 2011-11

Degree: Doctor of Philosophy

Degree level: Doctoral

Abstract: 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-glycoproteinP-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 polyethylene oxide-block-polyε-caprolactonePEO-b-PCL and PEO-b-polyα-benzyl-ε-caprolactone PEO-b-PBCL blockcopolymers 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 inthe 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.

Language: English

DOI: doi:10.7939-R35T2F

Rights: License granted by ZIYAD BINKHATHLAN ziyad@ualberta.ca 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.





Author: Binkhathlan, Ziyad

Source: https://era.library.ualberta.ca/


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University of Alberta Development of block copolymer based nanocarriers for the solubilization and delivery of valspodar by ZIYAD BINKHATHLAN A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PHARMACEUTICAL SCIENCES Faculty of Pharmacy and Pharmaceutical Sciences ©Ziyad Binkhathlan Fall 2011 Edmonton, Alberta 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 these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the authors prior written permission. Dedication I dedicate this thesis to my beloved mother, who has always been the main source of motivation for me; to my dear wife who has been in my side all the way with her love, support, and patience; and to my wonderful kids Saud and Yara. ABSTRACT 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 t...





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