Stimuli-Responsive Gene Vectors Based On Poss Core For Effcient Gene Delivery

Gene therapy is a therapeutic method that can insert the desired therapeutic genes into right cell to produce right protein. It is a very promising strategy, especially in the treatment of genetic diseases, cancer, viral infections and cardiovascular disease. Design and Synthesis of gene vectors with low toxicity and high transfection efficiency is a most urgent task for gene therapy. Compared with viral vectors and cationic liposomes, polycations, as the main type of nonviral gene vectors, have advantages on low host immunogenicity and mass production.POSS, as an kind of biocompatible core, with the unique cage-shaped provides an opportunity to design and synthesis of star-shaped polycations. Compared with linear polycations, star-shaped gene vectors with dense molecular architectures and flexible tailored structure have low cytotoxicity. Nonviral vectors must overcome multiple extracellular and intracellular barriers, such as enzymatic degradation, nonspecific uptake by reticuloendothelial system (RES) and premature release of DNA. Stimuli-responsive gene vectors can overcome the barriers by transform the molecular of vectors under the specific extra-or intracellular stimuli. By utilizing the extra-and intracellular environments (biological triggers), stimuli-responsive gene vectors can obtain a higher transfection efficiency. Combining these two aspects, we design the stimuli-responsive gene vectors based on POSS core.The bioreducible star-shaped gene vector (POSS-(SS-PDMAEMA)8) with well-defined structure and relatively narrow molecular weight distribution was synthesized via atom transfer radical polymerization (ATRP) of (2-dimethyla mino) ethyl methacrylate (DMAEMA) from a polyhedral oligomeric silsesquioxane (POSS) macroinitiator. POSS-(SS-PDMAEMA)8was composed of a biocompatible POSS core and eight disulfide-linked PDMAEMA arms, wherein the PDMAEMA chain length could be adjusted by controlling polymerization time. POSS-(SS-PDMAEMA)8can effectively bind pDNA into uniform nanocomplexes with appropriate particle size and zeta potential. The incorporation of disulfide bridges gave the POSS-(SS-PDMAEMA)8material facile bioreducibility. In comparison with POSS-(PDMAEMA)8without disulfide linkage, POSS-(SS-PDMAEMA)8exhibited much lower cytotoxicity and substantially higher transfection efficiency.A pH-responsive star-shaped gene vector, POSS-PGKA8, were prepared via atom transfer radical polymerization (ATRP) of glycidyl methacrylate (GMA) from a POSS-based macroinitiator and post-modified. Because of the introduction of ketal, POSS-PGKA8can be acid-hydrolyzed in endosome and then degraded to be oligomer. POSS-PGKA8can bind DNA into condensed nanoparticles which can earlily enter into the cell and decrease the cytotoxicity of the nanopaticles.