Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
ACS Appl Mater Interfaces. 2020 Apr 1;12(13):14825-14838. doi: 10.1021/acsami.9b22394. Epub 2020 Mar 23.
Cationic polymers condense nucleic acids into nanosized complexes (polyplexes) that are widely explored for nonviral gene delivery, but their strong electrostatic binding with DNA causes inefficient intracellular gene release and translation and thereby unsatisfactory gene transfection efficiencies. Facilitated intracellular dissociation of polyplexes by making the polymer undergo positive-to-negative/neutral charge reversal can effectively solve these problems, but they must be sufficiently stable during the delivery. Herein, we report the first glutathione (GSH)-specific intracellular labile polyplexes for cancer-targeted gene delivery. The polymers are made from -(2,4-dinitrophenyloxybenzyl)-ammonium cationic moieties, whose -2,4-dinitrophenyl ether is cleaved specifically by GSH, rather than other biological thiols, triggering the conversion of the ammonium cation into the carboxylate anion and thus the fast intracellular DNA release of the polyplexes. Furthermore, the polyplexes coated with PEG-functionalized lipids are stable in biological fluids to gain long blood circulation for tumor accumulation. Thus, the efficient tumor accumulation and cell transfection of the polyplexes loaded with the tumor suicide gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) give rise to potent antitumor activity similar to that of the first-line chemotherapy drug paclitaxel but with much less adverse effects.
阳离子聚合物将核酸浓缩成纳米大小的复合物（多聚物），广泛用于非病毒基因传递，但它们与 DNA 的强静电结合导致细胞内基因释放和翻译效率低下，从而导致基因转染效率不理想。通过使聚合物经历正到负/中性电荷反转来促进细胞内多聚物的解离，可以有效地解决这些问题，但它们在传递过程中必须足够稳定。本文报道了用于癌症靶向基因传递的第一个谷胱甘肽（GSH）特异性细胞内不稳定多聚物。这些聚合物由 -(2,4-二硝基苯氧基)苄基-铵阳离子部分组成，其 -2,4-二硝基苯醚可被 GSH 特异性切割，而不是其他生物硫醇，引发铵阳离子转化为羧酸盐阴离子，从而快速释放多聚物中的 DNA。此外，用 PEG 功能化脂质包覆的多聚物在生物流体中稳定，以获得长血液循环以促进肿瘤积累。因此，负载肿瘤自杀基因肿瘤坏死因子相关凋亡诱导配体（TRAIL）的多聚物具有高效的肿瘤积累和细胞转染作用，其抗肿瘤活性与一线化疗药物紫杉醇相当，但副作用要小得多。
