【摘要】 人类多种疾病都与基因的结构或功能改变密切相关,基因治疗已经成为改善人类健康的新兴医学治疗手段,基因治疗的关键在于构筑高效的基因载体.发展生物可降解、具有高转染效率和低毒性的阳离子聚合物基因载体已经成为当今该领域的主要任务.本文主要介绍了对细胞内外的环境差异和外界刺激具有响应性的阳离子聚合物基因载体的合成方法,实现DNA在细胞内的有效释放;构筑不同拓扑结构的聚合物,运用聚合物的拓扑结构来调节DNA与聚合物组装复合体形貌,实现DNA的可控压缩和提高载体的转染效率;通过两亲性阳离子聚合物的自组装形成稳定的阳离子纳米胶束,增加聚合物表面电荷密度,从而有效增强聚合物和DNA结合能力,实现低正负电荷比条件下的DNA压缩和基因的高效表达.更多还原

【Abstract】 Since gene therapy has the potential to alter expression of any gene of interest, itoffers tremendous promise for treating various human diseases including genetic disorders, cancers, viral infections, and cardiovascular diseases. To construct a suitable vector for transferring the therapeutic gene into the target cells of patients is important for achieving successful gene therapy. Cationic polymers have become one of the most promising synthetic vectors for gene transfection in biotechnology over the past two decades because of their advantages of simple preparation and modification. However, they have failed to enter clinical trials due to their low gene transfection efficacy by far. This review highlights some research work on developing Michael addition reaction, thiol-coupling reaction and thiol-exchange reaction for the preparation of stimuli-responsive polymers for helping the release of DNA inside cell and enhancing gene transfection; the fabrication of bioreducible cationic polymers with different topologies(linear structure, branched structure, and hyperbranched structure) via Michael addition reaction for tuning the morphology of the formed polymer/DNA polyplex to increase the cell-uptake and gene transfection; the design of newmethods for making the formed polyplex stable in blood system and for long blood circulation time, which can highly increase gene transfection in vivo. On the other hand, for most of the cationic polymers, their binding affinity with plasmid DNA is very weak. Therefore, a large excess of cationic polymer is typically required to achieve a complete DNA condensation, which results in high cytotoxicity and instability of the blood system. Herein, we also highlight the methods for the preparation of a novel class of bioreducible cationic nanomicelles with high surface charge using disulfide bonds to connect the cationic shells to the hydrophobic cores, and the bioreducible nanomicelles thus formed with very high binding affinity to DNA, and they can completely condense DNA even at N/P ratio of 1. The resulting nanomicelles/DNA polyplexes exhibit high biocompatibility and perform very effectively as an efficient gene delivery system, so its gene transfection efficiency is close to that of virus. Therefore, the new bioreducible cationic polymer nanomicelles have many potential applications in gene therapy.更多还原