Stimuli-responsive polymers and their applications in gene delivery

Polymeric gene delivery is introducing specific genes to enhance or silence gene expression using synthesized polymers which have low immunogenicity and good biocompatibility. This dissertations specifically focused on the synthesis and characterization of stimuli-responsive polymers for gene delivery. The polymers are designed to respond to specific biological stimuli such as redox potential and pH changes. In the first stimuli-responsive polymer, a reducible poly(L-lysine) (RPLL) was constructed and mediated gene delivery. Polyplex, polymer/gene complex, biocompatibility can be improved by using amino acids as nontoxic building blocks.#1;To synthesize an amino-acid-based reducible polymer, a decapeptide composed of lysine and cysteine (Cys-Lys8-Cys) has been selected due to primary amines and sulfhydryl functional groups, respectively. A reducible polymer introduced with disulfide bonds enables control of the rate of biodegradation and decomplexation of polyplex which will impact plasmid DNA (pDNA) release. In the second stimuli-responsive polymer, a pH-dependent polymeric-mediated gene delivery was conducted via PLL grafted with either mono-L-histidine (PLL-g-mHis) or poly(L-histidine) (PLL-g-PHis). The pH-sensitive ionizable groups in histidine were used as an endosomolytic agent to construct a pH-sensitive polymeric gene carrier. Two types of histidine grafted PLL, PLL-g-mHis and PLL-g-PHis, were synthesized with the same number of imidazole groups to compare the effective arrangement of histidine in terms of iv #1; endosomolytic activity and transfection efficiency. A wide range of observations have been made to conclude that a stimuli-sensitive property in polymer imparts a rapid response to specific stimulus compared to a nonsensitive polymer and the improved gene transfer activity#1;shows much promise for gene delivery. Since gene carriers have been applied in cancer gene therapy to safely and efficiently deliver a therapeutic gene into the target site, these stimuli-sensitive polymers will bring efficient translation levels of the therapeutic protein to treat cancer. Therefore, it is essential to further investigate the gene expression in vivo applications in an engaging and accessible way.#1