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Permanent link (DOI): https://doi.org/10.7939/R3VT1GZ32

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Development of polymer and lipid based nano-delivery systems for targeted cancer chemotherapy Open Access

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Other title
Subject/Keyword
peptide
liposomes
chemotherapy
polymeric micelle
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Shahin, Mostafa H
Supervisor and department
Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Lai, Raymond (Department of Laboratory Medicine and Pathology)
Lobenberg, Raimer (Faculty of Pharmacy and Pharmaceutical Sciences)
Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
Kaur, Kamaljit (Faculty of Pharmacy and Pharmaceutical Sciences)
Badea, IIdiko (College of Pharmacy, University of Saskatchewan)
Velazquez, Carlos (Faculty of Pharmacy and Pharmaceutical Sciences)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2012-09-27T08:55:23Z
Graduation date
2012-09
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Conventional chemotherapy agents can kill tumor cells and inhibit tumor growth, but they produce severe side effects on normal cells at the same time. To shift the balance towards tumoral effects, it would be desirable to direct the anti-cancer drug towards tumor while restricting drug access to normal tissues. The main objective of this thesis was to develop tumor targeted drug delivery system that can take on this task and as a result, improve the specificity and anticancer activity of the incorporated anticancer drugs towards tumor. To this end, lipid and block copolymer based nano-delivery systems of two conventional anti-cancer agents doxorubicin (DOX) and paclitaxel (PTX) are developed, respectively, and modified on their surface with a 12mer breast tumor interacting peptide, namely p160, or its engineered derivatives developed in our research team. The effect of peptide decoration on the specific interaction as well as anti-cancer activity of developed nano-formulations against human breast tumor cells over normal epithelial breast cells or endothelial cells was characterized, in vitro. In this study, micelles of poly(ethylene oxide)-b-poly(-caprolactone) were prepared and modified with either c(RGDfK) or p160 and loaded with paclitaxel (PTX). Peptide decoration enhanced the selective cytotoxicity of encapsulated PTX against cancer cells over normal cells. The extent of this increase in cancer cell specificity for encapsulated PTX was more for p160-modified micelles. At the end, the anti-cancer activity of liposomal formulations of DOX, having different density of an engineered breast tumor targeting peptide, namely p-18-4, was assessed in vitro for cellular uptake and selective cytotoxicity, and in vivo using animal model of human breast tumor xenograft and compared to that for liposomal formulations of DOX with no peptide decoration. Liposomal DOX formulations bearing low p18-4 density showed better in vitro selective cytotoxicity and in vivo therapeutic efficacy. Our results points to the potential of p160 and its engineered derivatives as efficient ligands on lipid and block copolymer based nanocarriers for active targeting of anticancer agents to breast tumors. The results also show the success of this strategy in enhancing the specific anti-cancer effects of the incorporated drug against breast tumor models.
Language
English
DOI
doi:10.7939/R3VT1GZ32
Rights
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 author's prior written permission.
Citation for previous publication
Shahin, M. and Lavasanifar A., Novel self-associating poly(ethylene oxide)-b-poly(epsilon-caprolactone) based drug conjugates and nano-containers for paclitaxel delivery. Int J Pharm, 2010. 389(1-2): p. 213-22.Shahin M., Ahmed S., Kaur K., Lavasanifar A: Decoration of polymeric micelles with cancer cell specific peptide ligands for active targeting of paclitaxel. Biomaterials. 2011, 32 (22): p. 5123-33.

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