Department of Chemistry and Biochemistry, Concordia University, Montréal, Québec, Canada H4B 1R6.
Mol Pharm. 2020 Oct 5;17(10):3979-3989. doi: 10.1021/acs.molpharmaceut.0c00767. Epub 2020 Sep 10.
Gene therapy holds great promise for the treatment of acquired genetic disorders such as cancer with reduced side effects compared to chemotherapy. For gene therapy to be successful, it is crucial to develop efficient and nontoxic gene carriers to overcome the poor stability and low cellular uptake of nucleic acid-based therapeutic agents. Here, we report a new and versatile approach exploring a combination of hydrophobic modifications and dual-stimuli-responsive degradation (SRD) for controlled gene delivery with amphiphilic block copolymer-based nanocarriers. The block copolymer, synthesized by atom transfer radical polymerization, is designed with an acid-labile acetal linkage at the block junction and a pendant disulfide group in the hydrophobic block. The incorporation of labile linkages enables both disulfide-core-cross-linking and dual-location dual-acid/reduction-responsive degradation (DL-DSRD). Furthermore, the disulfide linkages integrated as hydrophobic moieties facilitate the nucleic acids to condense into nanometer-sized micelleplexes through electrostatic interactions of pendant dimethylamino groups with the anionic phosphate groups of the nucleic acids. Our preliminary results demonstrate that the DL-DSRD approach through hydrophobic modification is a robust platform in the development of gene delivery systems with enhanced colloidal stability, reduced cytotoxicity, and improved gene transfection efficiency.
基因治疗为治疗后天性遗传疾病（如癌症）提供了巨大的希望，与化疗相比，其副作用较小。为了使基因治疗成功，开发高效、无毒的基因载体以克服核酸治疗剂的稳定性差和细胞摄取率低至关重要。在这里，我们报告了一种新的多功能方法，探索了疏水性修饰和双重刺激响应降解（SRD）的组合，以使用基于两亲嵌段共聚物的纳米载体进行受控基因传递。该嵌段共聚物通过原子转移自由基聚合合成，在嵌段连接处设计有酸不稳定的缩醛键，在疏水性嵌段中有一个侧挂的二硫键。易断键的引入使得二硫键核交联和双位置双酸/还原响应降解（DL-DSRD）都成为可能。此外，二硫键作为疏水性部分整合，通过侧挂的二甲氨基与核酸的阴离子磷酸基团之间的静电相互作用，促进核酸凝聚成纳米尺寸的胶束。我们的初步结果表明，通过疏水性修饰的 DL-DSRD 方法是一种强大的基因传递系统开发平台，具有增强的胶体稳定性、降低的细胞毒性和提高的基因转染效率。
