Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Department of Biology, University of Texas Rio Grande Valley, Edinburg, Texas 78539, United States.
ACS Macro Lett. 2022 Apr 19;11(4):588-594. doi: 10.1021/acsmacrolett.2c00015. Epub 2022 Apr 8.
Polymer-based gene delivery relies on the binding, protection, and final release of nucleic acid cargo using polycations. Engineering polymeric vectors, by exploring novel topologies and cationic moieties, is a promising avenue to improve their performance, which hinges on the development of simple synthetic methods that allow facile preparation. In this work, we focus on cationic micelles formed from block polymers, which are examined as promising gene compaction agents and carriers. In this study, we report the synthesis and assembly of six amphiphilic poly(-butyl acrylate)--poly(cationic acrylamide) diblock polymers with different types of cationic groups ((dialkyl)amine, morpholine, or imidazole) in their hydrophilic corona. The polycations were obtained through the parallel postpolymerization modification of a poly(-butyl acrylate)--poly(pentafluorophenyl acrylate) reactive scaffold, which granted diblock polymers with equivalent degrees of polymerization and subsequent quantitative functionalization with cations of different p. Ultrasound-assisted direct dissolution of the polycations in different aqueous buffers (pH = 1-7) afforded micellar structures with low size dispersities and hydrodynamic radii below 100 nm. The formation and properties of micelle-DNA complexes ("micelleplexes") were explored via DLS, zeta potential, and dye-exclusion assays revealing that binding is influenced by the cation type present in the micelle corona where bulkiness and p are the drivers of micelleplex formation. Combining parallel synthesis strategies with simple direct dissolution formulation opens opportunities to optimize and expand the range of micelle delivery vehicles available by facile tuning of the composition of the cationic micelle corona.
基于聚合物的基因传递依赖于使用聚阳离子结合、保护和最终释放核酸货物。通过探索新的拓扑结构和阳离子基团来设计聚合物载体是提高其性能的一种有前途的途径，这取决于开发简单的合成方法，以便于制备。在这项工作中，我们专注于由嵌段聚合物形成的阳离子胶束，这些胶束被认为是有前途的基因紧缩剂和载体。在这项研究中，我们报告了六种两亲性聚（-丁基丙烯酸酯）-聚（阳离子丙烯酰胺）嵌段聚合物的合成和组装，它们在亲水冠中具有不同类型的阳离子基团（（二烷基）胺、吗啉或咪唑）。聚阳离子是通过聚（-丁基丙烯酸酯）-聚（五氟苯丙烯酸酯）反应性支架的平行后聚合修饰获得的，这使嵌段聚合物具有相同的聚合度，并随后用不同 p 值的阳离子进行定量功能化。在不同的水性缓冲液（pH = 1-7）中，通过超声辅助直接溶解聚阳离子，可得到尺寸分散性低且流体力学半径低于 100nm 的胶束结构。通过动态光散射（DLS）、zeta 电位和染料排除实验探索了胶束-DNA 复合物（“胶束复合物”）的形成和性质，结果表明，结合受胶束冠中存在的阳离子类型的影响，其中体积大和 p 值是胶束复合物形成的驱动力。将平行合成策略与简单的直接溶解配方相结合，为优化和扩展可用的胶束递药载体范围提供了机会，通过简单地调节阳离子胶束冠的组成来实现。
