Grimme Christian J, Hanson Mckenna G, Corcoran Louis G, Reineke Theresa M
Department of Chemical Engineering & Materials Science, University of Minnesota, 421 Washington Avenue SE, Minneapolis, Minnesota 55455, United States.
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Biomacromolecules. 2022 Aug 8;23(8):3257-3271. doi: 10.1021/acs.biomac.2c00338. Epub 2022 Jul 21.
Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate) (OD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (ODB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an O brush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides. The DB micelleplexes promoted the largest gene silencing, internalization, and tolerable toxicity while the ODB micelleplexes displayed enhanced colloidal stability and highly efficient payload trafficking despite having lower cellular uptake. Overall, this work demonstrates that cationic micelles are superior delivery vehicles for ASOs denoting the importance of vehicle architecture in biological performance.
在此，我们研究了一种短单链反义寡核苷酸（ASO）负载物与四种形成两种结构变体（多聚体和胶束复合物）的聚合物衍生物的络合及生物递送情况：一种均聚物聚（甲基丙烯酸2-二甲基氨基乙酯）（D）、一种二嵌段聚合物聚（乙二醇）甲基醚甲基丙烯酸酯-聚（甲基丙烯酸2-二甲基氨基乙酯）（OD），以及两种形成胶束的变体，聚（甲基丙烯酸2-二甲基氨基乙酯）-聚（甲基丙烯酸丁酯）（DB）和聚（乙二醇）甲基醚甲基丙烯酸酯-聚（甲基丙烯酸2-二甲基氨基乙酯）-聚（甲基丙烯酸丁酯）（ODB）。多聚体和胶束复合物均能与ASO络合，并且引入O型刷可增强胶体稳定性。胶束复合物由未负载胶束的大小和形状决定，且胶束与ASO的络合对制剂/混合顺序不敏感，这使得在包装短寡核苷酸时操作简便、具有通用性且可重复。DB胶束复合物促进了最大程度的基因沉默、内化以及可耐受的毒性，而ODB胶束复合物尽管细胞摄取较低，但显示出增强的胶体稳定性和高效的负载物转运。总体而言，这项工作表明阳离子胶束是ASO的优异递送载体，这表明载体结构在生物学性能方面的重要性。
