Zhang Junwei, Cui Jiajia, Deng Yang, Jiang Zhaozhong, Saltzman W Mark
Department of Chemical and Environmental Engineering, Yale University, 55 Prospect Street, New Haven, CT 06511, USA.
Department of Biomedical Engineering, Yale University, 55 Prospect Street, New Haven, CT 06511, USA.
ACS Biomater Sci Eng. 2016 Nov 14;2(11):2080-2089. doi: 10.1021/acsbiomaterials.6b00502. Epub 2016 Sep 26.
Cationic polymers are used for non-viral gene delivery, but current materials lack the functionality to address the multiple barriers involved in gene delivery. Here we describe the rational design and synthesis of a new family of quaterpolymers with unprecedented multifunctionality: acid sensitivity, low cationic charge, high hydrophobicity, and biodegradability, all of which are essential for efficient and safe gene delivery. The polymers were synthesized via lipase-catalyzed polymerization of ortho ester diester, lactone, dialkyl diester, and amino diol monomers. Polymers containing ortho ester groups exhibited acid-sensitive degradation at endosomal pH (4~5), facilitated efficient endosomal escape and unpackaging of the genes, and were efficient in delivering genetic materials to HEK293 cells, human glioma cells, primary mouse melanoma cells, and human umbilical vein endothelial cells (HUVECs). We also developed a highly efficient lyophilized formulation of the nanoparticles, which could be stored for a month without loss of efficiency.
阳离子聚合物用于非病毒基因递送，但目前的材料缺乏解决基因递送中涉及的多种障碍的功能。在此，我们描述了一类具有前所未有的多功能性的新型四聚体聚合物的合理设计与合成：酸敏感性、低阳离子电荷、高疏水性和生物可降解性，所有这些对于高效且安全的基因递送都是必不可少的。这些聚合物是通过脂肪酶催化的原酸酯二酯、内酯、二烷基二酯和氨基二醇单体的聚合反应合成的。含有原酸酯基团的聚合物在内体pH值（4~5）下表现出酸敏感降解，促进了基因的高效内体逃逸和解包，并能有效地将遗传物质递送至人胚肾293细胞、人胶质瘤细胞、原代小鼠黑色素瘤细胞和人脐静脉内皮细胞（HUVECs）。我们还开发了一种高效的纳米颗粒冻干制剂，其可储存一个月而不损失效率。
