Synthesis of Biodegradable Polyester-Modified Reduction-Sensitive Block Copolymers as Efficient Gene Vectors

Gene delivery has been the subject of much research over the past 15 years due to its potential to treat intractable diseases by introducing DNA into the host cells. Cationic polymers have shown promise for the prospect of gene delivery. However, most synthetic vectors lack the transfection efficiency necessary for clinical use. Therefore, the goal of this project is to synthesize a polymeric delivery system that can efficiently introduce DNA into host cells. We will report the synthesis of poly(ε-caprolactone) (PCL) and poly(glycidyl methacrylate) (pGMA) copolymers associated by a disulfide bond. The reactive epoxy groups in the side chain of the GMA block are decorated with the oligoamine tetraethylenepentamine (TEPA) to generate the polycationic, reduction-sensitive PCL-SS-P(GMA-TEPA) polymers. The effect of chain length of the hydrophobic PCL segment on DNA binding and salt stability will be investigated. We anticipate that the introduction of the PCL segment will enhance the DNA condensation ability and salt stability of the cationic polymer. To test this hypothesis, agarose gel retardation assays will be conducted coupled to size analysis of the DNA-polymer complexes. The transfection efficiency will be determined by an in vitro luciferase assay using HeLa cells as a model. The degradation of the disulfide linkage in the intracellular reducing environment will detach the PCL moiety and facilitate the release of DNA. Therefore, we expect that these reduction-sensitive polymers will exhibit higher transfection and constitute a more efficient gene delivery system.