Liu Shuai, Jia Huiting, Yang Jixiang, Pan Jianping, Liang Huiyun, Zeng Liheng, Zhou Hao, Chen Jiatong, Guo Tianying
Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
Department of Biochemistry and Molecular Biology, College of Life Science, Nankai University, Tianjin 300071, China.
ACS Macro Lett. 2018 Jul 17;7(7):868-874. doi: 10.1021/acsmacrolett.8b00374. Epub 2018 Jul 2.
Amines have been extensively involved in vector design thus far, however, their clinical translation has been impeded by several obstacles: cytotoxicity, polyplex serum instability and low efficacy in vivo. In pursuit of functional groups to substitute amines in vector design to address these disadvantages is of great significance. Herein, we report well-tailored noncationic copolymers that contain hydrophilic, hydrophobic, and zinc coordinative moieties through reversible addition-fragmentation chain transfer (RAFT) polymerization for efficient and safe gene delivery. These polymers are capable of condensing DNA, enabling the formation of uncharged polyplexes. Especially, the zinc coordinative ligand can simultaneously benefit strong DNA binding, robust cellular uptake, efficacious endosomal destabilization, low cytotoxicity, and avoidance of serum protein adsorption. The coordinative module holds great promise to substitute amines and inspires the development of next-generation gene vectors. More importantly, the coordinative copolymers illuminate the possibility and potential of noncationic gene delivery systems for clinical applications.
到目前为止，胺类已广泛应用于载体设计中，然而，它们的临床转化受到了几个障碍的阻碍：细胞毒性、多聚体血清不稳定性和体内低疗效。寻找能在载体设计中替代胺类的官能团以克服这些缺点具有重要意义。在此，我们报道了通过可逆加成-断裂链转移（RAFT）聚合制备的精心设计的非阳离子共聚物，其含有亲水、疏水和锌配位部分，用于高效、安全的基因递送。这些聚合物能够凝聚DNA，形成不带电荷的多聚体。特别是，锌配位配体可同时有利于强DNA结合、强大的细胞摄取、有效的内体去稳定化、低细胞毒性以及避免血清蛋白吸附。这种配位模块有望替代胺类，并推动下一代基因载体的发展。更重要的是，这种配位共聚物揭示了非阳离子基因递送系统用于临床应用的可能性和潜力。
