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Lipid modification of polymeric nanocarriers for drug and siRNA delivery Open Access


Other title
Amphotericin B
Type of item
Degree grantor
University of Alberta
Author or creator
Falamarzian, Arash
Supervisor and department
Lavasanifar, Afsaneh (Pharmacy and Pharmaceutical Sciences)
Uludag, Hasan (Chemical and Material Engineering)
Examining committee member and department
Lai, Raymond (Labratory Medicine and Pathology)
Uludag, Hasan (Chemical and Material Engineering)
Siraki, Arno (Pharmacy and Pharmaceutical Sciences)
Kaur, Kamaljit (Pharmacy and Pharmaceutical Sciences)
Prakash, Satya (Biomedical Engineering, Faculty of Medicine, McGill University)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
Doctor of Philosophy
Degree level
The use of nanotechnology in pharmaceutical development has progressed significantly in recent decades. This rapid advancement is driven by crucial need for improving the performance of present diagnostic and therapeutic modalities, as well as development of a new class of delivery systems for complex entities such as genes and proteins. Nanocarriers currently in use for the delivery of drugs and genetic materials can be generally divided to two categories: those made from lipids and those made from synthetic or natural polymers. Although lipid-based carriers are generally regarded to be safe and efficient, they do not possess sufficient chemical flexibility to fit individual requirements in delivery. In this thesis, we have explored lipid-substitution of three different polymer-based nanocarriers as means to develop optimum structures for drug as well as siRNA delivery. For the delivery of a potent amphiphilic antifungal drug, amphotericin B (AmB), lipid modification (particularly cholesteryl modification) of the core structure in poly(ethylene oxide)-poly(caprolactone) micelles was proved to be efficient in enhancing the solubility while reducing the hemolytic activity of encapsulated AmB. On the other hand, lipid modification of low molecular weight (2 kDa) polyethyleneimine (PEI2) has enhanced the properties of the nanocarriers in the delivery of STAT3-siRNA in wild type and resistant breast cancer cell models leading to an improved anti-cancer efficacy in combination with chemotherapeutic drugs, i.e. DOX and PTX. Finally, cholesteryl modification of poly(ethylene oxide)-poly(caprolactone-g-spermine) enhanced the properties of these nanocarriers for in vivo delivery of siRNA. This modification enhanced the stability, safety and cellular uptake of complexed siRNA leading to better silencing activity at the mRNA level. Overall, our results pointed to the positive impact of lipid modification in enhancing the properties of polymeric nanocarriers leading to viable formulations for effective delivery of AmB and siRNA therapeutics.
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
Xiong XB, Falamarzian A, Garg SM, Lavasanifar A. Engineering of amphiphilic block copolymers for polymeric micellar drug and gene delivery. J Control Release 2011;155:248-61.Falamarzian A, Lavasanifar A. Chemical Modification of Hydrophobic Block in Poly(Ethylene Oxide) Poly(Caprolactone) Based Nanocarriers: Effect on the Solubilization and Hemolytic Activity of Amphotericin B. Macromol Biosci.Falamarzian A, Xiong XB, Uludag H, Lavasanifar A. Polymeric micelles for siRNA delivery. J Drug Deliv Sci Tec 2012;22:43-54.Falamarzian A, Lavasanifar A. Optimization of the hydrophobic domain in poly(ethylene oxide)-poly(varepsilon-caprolactone) based nano-carriers for the solubilization and delivery of Amphotericin B. Colloids Surf B Biointerfaces 2010;81:313-20.

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