College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Soochow University, Suzhou 215123, P. R. China.
J Mater Chem B. 2019 Feb 7;7(5):786-795. doi: 10.1039/c8tb02772b. Epub 2019 Jan 9.
Zwitterionic polymers are a class of polymers that acts as both Lewis base and Lewis acid in solution. These polymers not only have excellent properties of hydration, anti-bacterial adhesion, charge reversal and easy chemical modification, but also have characteristics of long-term circulation and suppress nonspecific protein adsorption in vivo. Here, we describe a novel folate-targeted and acid-labile polymeric prodrug under the microenvironment of tumor cells, abbreviated as FA-P(MPC-co-PEGMA-BZ)-g-DOX, which was synthesized via a combination of reversible addition-fragmentation chain transfer (RAFT) copolymerization, Schiff-base reaction, Click chemistry, and a reaction between the amine group of doxorubicin (DOX) and aldehyde functionalities of P(MPC-co-PEGMA-BZ) pendants, wherein MPC and PEGMA-BZ represent 2-(methacryloyloxy)ethyl phosphorylcholine and polyethylene glycol methacrylate ester benzaldehyde, respectively. The polymeric prodrug could self-assemble into nanoparticles in an aqueous solution. The average particle size and morphologies of the prodrug nanoparticles were observed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. We also investigated the in vitro drug release behavior and observed rapid prodrug nanoparticle dissociation and drug release under a mildly acidic microenvironment. The methyl thiazolyl tetrazolium (MTT) assay verified that the P(MPC-co-PEGMA-BZ) copolymer possessed good biocompatibility and the FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticles showed higher cellular uptake than those prodrug nanoparticles without the FA moiety. The results of cytotoxicity and the intracellular uptake of non-folate/folate targeted prodrug nanoparticles further confirmed that FA-P(MPC-co-PEGMA-BZ)-g-DOX could be efficiently accumulated and rapidly internalized by HeLa cells due to the strong interaction between multivalent phosphorylcholine (PC) groups and cell membranes. This kind of multifunctional FA-P(MPC-co-PEGMA-BZ)-g-DOX prodrug nanoparticle with combined target-ability and pH responsiveness demonstrates promising potential for cancer chemotherapy.
两性离子聚合物是一类在溶液中既作为路易斯碱又作为路易斯酸的聚合物。这些聚合物不仅具有优异的水合、抗细菌黏附、电荷反转和易于化学修饰的性能，而且还具有在体内长期循环和抑制非特异性蛋白吸附的特性。在这里，我们描述了一种新型叶酸靶向的酸不稳定聚合物前药，缩写为 FA-P(MPC-co-PEGMA-BZ)-g-DOX，它是通过可逆加成-断裂链转移（RAFT）共聚、席夫碱反应、点击化学和阿霉素（DOX）的氨基与 P(MPC-co-PEGMA-BZ)侧基上的醛基之间的反应合成的，其中 MPC 和 PEGMA-BZ 分别代表 2-(甲基丙烯酰氧)乙基磷酸胆碱和聚乙二醇甲基丙烯酸酯酯苯甲醛。聚合物前药可以在水溶液中自组装成纳米颗粒。通过动态光散射（DLS）和透射电子显微镜（TEM）分别观察前药纳米颗粒的平均粒径和形态。我们还研究了体外药物释放行为，并观察到在温和酸性微环境下前药纳米颗粒快速解离和药物释放。噻唑蓝（MTT）测定法证实 P(MPC-co-PEGMA-BZ)共聚物具有良好的生物相容性，FA-P(MPC-co-PEGMA-BZ)-g-DOX 前药纳米颗粒比没有 FA 部分的前药纳米颗粒具有更高的细胞摄取率。非叶酸/叶酸靶向前药纳米颗粒的细胞毒性和细胞内摄取结果进一步证实，由于多价磷酸胆碱（PC）基团与细胞膜之间的强烈相互作用，FA-P(MPC-co-PEGMA-BZ)-g-DOX 能够被 HeLa 细胞有效积累并迅速内化。这种具有靶向性和 pH 响应性的多功能 FA-P(MPC-co-PEGMA-BZ)-g-DOX 前药纳米颗粒具有潜在的癌症化疗应用前景。
