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Permanent link (DOI): https://doi.org/10.7939/R3RD4B

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Carbohydrate and Phosphorylcholine based Polymers Prepared by Reversible Addition-Fragmentation Chain Transfer Polymerization for Gene Therapy Open Access

Descriptions

Other title
Subject/Keyword
Cationic Glycopolymers
Gene delivery
RAFT polymerization
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Ahmed, M
Supervisor and department
Narain, Ravin (Chemical and Materials Engineering)
Examining committee member and department
Stenzel Martinez (University of New South Wales)
Uludag Hasan (Chemical and Materials Engineering)
Li Dongyang (Chemical and Materials Engineering)
Zeng, Hongbo (Chemical and Materials Engineering)
Deyholos, Michael (Biological Sciences)
Department
Department of Chemical and Materials Engineering
Specialization
Chemical Engineering
Date accepted
2012-09-26T15:54:05Z
Graduation date
2012-09
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The study provides a comprehensive account on the development of novel synthetic carbohydrate and phosphorylcholine polymer based gene delivery vectors. Since the development and use of first non-viral vector for gene delivery applications, a wide range of polymers have been synthesized and studied for their gene delivery efficacies. With the advent of living radical polymerization, well-defined polymers with varying molecular weights, compositions and architectures have been synthesized and evaluated as potent gene delivery vectors. Reversible addition-fragmentation chain transfer polymerization (RAFT) has allowed the facile synthesis of tailor-made cationic polymers which are promising non-viral gene delivery vectors. Advanced structure-activity relationship studies between the polymers and gene expression have been possible due to the remarkable control in the design of these polymers via the RAFT process. In the first study, RAFT polymerization technique allows the successful synthesis of cationic glycopolymers containing pendant sugar moieties. A library of cationic glycopolymers of pre-determined molar masses and narrow polydispersities ranging from 3-30 kDa has been synthesized. These polymers differ from each other in their architectures (block versus random), molecular weights, and monomer ratios (carbohydrate to cationic segment). It is shown that the above-mentioned parameters can largely affect the toxicity, DNA condensation ability and gene delivery efficacy of these polymers. The effect of serum proteins on statistical and diblock copolymer based polyplexes and hence gene delivery efficacy is further studied. In the second study, 2-methacryloxyethyl phosphorylcholine (MPC) copolymers are studied for their ability to produce non-toxic and biocompatible materials. The cationic MPC copolymers of varying architectures (block versus random) are produced by RAFT polymerization technique. The copolymers produced are further evaluated for their, morphology, cellular uptake and gene delivery efficacy in the presence and absence of serum. The polymers with branched architecture are reported to be superior gene delivery vectors as compared to their linear analogues. In another study, hyperbranched glycopolymers of varying molecular weights and compositions are synthesized via reversible addition fragmentation chain transfer (RAFT) process and are further explored for their gene expression in vitro. Galactose based hyperbranched polymers are compared to glucose-derived hyperbranched polymers for their cellular uptake, toxicity, lectin interactions and gene expression. Furthermore, the cellular uptake and gene expression are studied in two different cell lines in the presence of lectins. The superior gene expression of linear statistical polymers is also accompanied by their significant aggregation in serum containing media. To solve this problem, carbohydrate and phosphorylcholine based cationic polymers having a novel architecture, different compositions and varying molecular weights are produced and are termed as cationic ‘block-statistical’ copolymers. These cationic copolymers are evaluated for their gene delivery efficacies, interactions with serum protein, cellular uptake and nuclear localization ability. In addition, MPC based ‘block-statistical’ copolymers and their sugar incorporated analogues are prepared and are compared with their statistical analogues for serum interactions and gene expression.
Language
English
DOI
doi:10.7939/R3RD4B
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
Ahmed, M.; Narain, R. The effect of polymer architecture, composition, and molecular weight on the properties of glycopolymer-based non-viral gene delivery systems. Biomaterials 2011, 32, 5279.Ahmed, M.; Bhuchar, N.; Narain, R. Well-Controlled Cationic Water-Soluble Phospholipid Polymer-DNA Nanocomplexes for Gene Delivery. Bioconjugate Chem. 2011, 22, 1228Ahmed, M.; Narain, R. The effect of molecular weight, compositions and lectin type on the properties of hyperbranched glycopolymers as non-viral gene delivery systems. Biomaterials 2012, 33, 3990.Ahmed, M.; Jawanda, M.; Ishihara, K.; Narain, R. Carbohydrate and Phosphorylcholine Polymer based Gene Delivery Vectors with Novel Molecular Architecture. Biomaterial, 2012, 33, 7858

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