1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Nankai University, Tianjin 300071, P.R. China.
2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, P.R. China.
Theranostics. 2016 Jun 6;6(9):1277-92. doi: 10.7150/thno.15133. eCollection 2016.
Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.
化疗在癌症治疗中已被证明会对健康组织产生一些副作用，并导致肿瘤细胞产生多药耐药性，这极大地限制了治疗效果。为了解决这些限制并实现更好的治疗效果，基于纳米颗粒平台的联合治疗通过同时将不同的药物递送到同一目的地并产生协同作用，提供了一种有前途的方法。在这项研究中，通过静电相互作用和聚乙二醇-嵌段-聚（赖氨酸-共-赖氨酸-苯硼酸）（PEG-PLys/PBA）与 EGCG 之间的苯硼酸-儿茶酚相互作用，构建了一种新型的基于绿茶儿茶素的聚离子复合物（PIC）胶束，该胶束负载阿霉素（DOX）和（-）-表没食子儿茶素-3-O-没食子酸酯（EGCG）。DOX 通过与 EGCG 的π-π堆积相互作用共同负载在 PIC 胶束中。苯硼酸-儿茶酚相互作用赋予 PIC 胶束在生理条件下的高稳定性。此外，胶束核中苯硼酸-儿茶酚相互作用的酸可裂解性对以协同作用将 EGCG 和 DOX 递送到同一目的地具有重要意义。此外，得益于 EGCG 的清除氧自由基活性，根据心脏的组织病理学分析，胶束核中 EGCG 和 DOX 的联合治疗可以保护心肌细胞免受 DOX 引起的心脏毒性。由于 EGCG 对 P 糖蛋白（P-gp）活性的调节，这种 PIC 胶束可以有效地逆转肿瘤细胞的多药耐药性。这些结果表明，基于 EGCG 的 PIC 胶束可以有效地克服 DOX 诱导的心脏毒性和多药耐药性。
