CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
J Am Chem Soc. 2013 Nov 20;135(46):17617-29. doi: 10.1021/ja409686x. Epub 2013 Nov 7.
Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.
嵌段共聚物（BCPs）的溶液自组装通常会生成球体、棒状和囊泡。由于它们倾向于弯曲成闭合双层，因此难以通过自下而上的方法来制备稳定的平面纳米结构。这种形态上的空缺使得研究 BCP 纳米载体与细胞相互作用中的形状效应不完整。此外，具有内置药物传递功能和几何形状优化性能的单个 BCP 组装体的制造仍然是一个主要挑战。我们证明，PEG-b-PCPTM 聚前药两亲物，其中 PEG 是聚乙二醇，PCPTM 是可还原裂解的喜树碱（CPT）前药单体的聚合嵌段，载药量超过 50wt%，可以自组装成包括球体、大复合囊泡、光滑圆盘和具有刺状边缘的前所未有的交错层状在内的四种均匀纳米结构。交错层状比其他三种纳米结构类型表现更好，具有延长的血液循环持续时间、最快的细胞摄取和独特的内化途径。我们还探索了形状调制的 CPT 释放动力学、纳米结构降解和体外细胞毒性。聚前药两亲物的可控分层组织和形状可调的生物学性能为探索具有改进疗效的下一代基于 BCP 的药物传递系统开辟了新的前景。
