Abstract

Gene therapy holds a great promise in the treatment of acquired genetic disorders such as cancer because it shows fewer side effects compared to chemotherapy. In order for gene therapy to be successful, however, it is crucial to develop efficient and non-toxic gene carriers to overcome poor in vivo stability and low cellular uptake of nucleic acid therapeutic agents. My Master’s thesis research mainly focuses on the development of a new approach exploring a combination of hydrophobic modification with stimuli-responsive degradation (SRD) to synthesize novel amphiphilic block copolymer-based nanocarriers for controlled gene delivery. The block copolymer synthesized by atom transfer radical polymerization is designed with an acid-labile acetal linkage at the block junction and pendant disulfide group in a hydrophobic block. The incorporation of labile linkages enables both dual-location dual-acid/reduction-responsive degradation (DL-DSRD) and in situ disulfide-core-crosslinking. Further, the disulfide pendants integrated as hydrophobic moieties facilitate to condense the nucleic acids into nanometer-sized micelleplexes through electrostatic interaction of pendant dimethylamino groups with the anionic phosphate groups of the nucleic acids. Our results demonstrate that the hydrophobic modification approach through DL-DSRD is a robust platform in the development of gene delivery systems with enhanced colloidal stability, reduced cytotoxicity, and improved gene transfection efficiency.
Further, my research is interested in the biological evaluation of delivery nanocarriers to investigate their cellular interactions with various biological systems for tumor-targeted delivery. Four SRD-exhibiting amphiphilic block copolymer micelles were chosen for not only their various chemical compositions but also different positions of labile linkages cleavable in response to acidic pH and glutathione. The results from cytotoxicity and cellular uptake assays reveal that polymer composition and arrangement of monomers play an important role to determine the biological fate of SRD-exhibiting nanocarriers.