Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA; Simpson Querrey Institute, Northwestern University, Chicago, IL, USA.
Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
J Control Release. 2018 Jul 28;282:90-100. doi: 10.1016/j.jconrel.2018.03.027. Epub 2018 Mar 28.
Polymer vesicles, i.e. polymersomes (PS), present unique nanostructures with an interior aqueous core that can encapsulate multiple independent cargos concurrently. However, the sequential release of such co-loaded actives remains a challenge. Here, we report the rational design and synthesis of oxidation-responsive shell-crosslinked PS with capability for the controlled, sequential release of encapsulated hydrophilic molecules and hydrogels. Amphiphilic brush block copolymers poly(oligo(ethylene glycol) methyl ether methacrylate)-b-poly(oligo(propylene sulfide) methacrylate) (POEGMA-POPSMA) were prepared to fabricate PS via self-assembly in aqueous solution. As a type of unique drug delivery vehicle, the interior of the PS was co-loaded with hydrophilic molecules and water-soluble poly(N-isopropylacrylamide) (PNIPAM) conjugates. Due to the thermosensitivity of PNIPAM, PNIPAM conjugates within the PS aqueous interior underwent a phase transition to form hydrogels in situ when the temperature was raised above the lower critical solution temperature (LCST) of PNIPAM. Via control of the overall shell permeability by oxidation, we realized the sequential release of two water-soluble payloads based on the assumption that hydrogels have much smaller membrane permeability than that of molecular cargos. The ability to control the timing of release of molecular dyes and PNIPAM-based hydrogels was also observed within live cells. Furthermore, leakage of hydrogels from the PS was effectively alleviated in comparison to molecular cargos, which would facilitate intracellular accumulation and prolonged retention of hydrogels within the cell cytoplasm. Thus, we demonstrate that the integration of responsive hydrogels into PS with crosslinkable membranes provides a facile and versatile technique to control the stability and release of water-soluble cargos for drug delivery purposes.
聚合物囊泡，即聚合物胶束（PS），具有独特的纳米结构，内部有一个水相核，可以同时包封多个独立的载药。然而，这种共载药物的顺序释放仍然是一个挑战。在这里，我们报告了氧化响应性壳交联 PS 的合理设计和合成，该 PS 具有控制和顺序释放包封亲水分子和水凝胶的能力。两亲性刷状嵌段共聚物聚（聚乙二醇甲醚甲基丙烯酸酯）-b-聚（聚丙硫醚甲基丙烯酸酯）（POEGMA-POPSMA）被制备用来通过在水溶液中自组装来制备 PS。作为一种独特的药物输送载体，PS 的内部共载有亲水分子和水溶性聚（N-异丙基丙烯酰胺）（PNIPAM）缀合物。由于 PNIPAM 的温敏性，当温度升高到 PNIPAM 的下临界溶液温度（LCST）以上时，PS 水相内部的 PNIPAM 缀合物会发生相转变，原位形成水凝胶。通过氧化控制整体壳通透性，我们实现了两种水溶性载药的顺序释放，假设水凝胶的膜通透性比分子载药小得多。我们还观察到在活细胞中，分子染料和基于 PNIPAM 的水凝胶的释放时间可以得到控制。此外，与分子载药相比，水凝胶从 PS 中的泄漏得到了有效缓解，这有利于水凝胶在细胞内的积累和在细胞质内的滞留时间延长。因此，我们证明了将响应性水凝胶整合到具有交联膜的 PS 中，为控制水溶性载药的稳定性和释放提供了一种简单而通用的技术，可用于药物输送。
