新型和厚朴酚高分子-PEG键合物的制备及其体内外抗肿瘤研究

Honokiol (HK) has showed potent anticancer activity and synergistic anticancer effect with other anticancer agent, but its water-insolubility makes its low bioavailability. Herein, we will design a novel type of polymer drug conjugates PHK-PEG- - the high molecular weight honokiol polymers (polyhonokiol,PHK) conjugated with two polyethylene glycol(PEG)chains via acetal bonds that can easily hydrolyze at acidic pH. PHK can be made by condensation polymerization of HK with divinyl ether comonomers contains acetal bonds.In aqueous conditon，PHK-PEG can form stable micelle and serves two roles - as an anticancer prodrug and a drug carrier. As an anticancer prodrug, PHK-PEG micelle will have a high and fixed HK-loading content, and released active HK in the intracellular acidic lysosomes environment. As drug carriers, PHK-PEG micell could carry other anticancer drugs, such as doxorubicin, and ship them into drug-resistant cells, greatly enhancing the cytotoxicity of the loaded drug. PHK-PEG will be a promising prototype that merits further study for cancer therapy. In this work, Following behaviors of PHK-PEG including the self-assembly behavior in water, in vitro and in vivo drug release properties，anticancer effects in vitro and in vivo will be carefully investigated, thus led to the establishment of a structure-activity relationship, which will be important for further exploration of the potential application of HK in the cancer therapy.

和厚朴酚（Honokiol,HK）具有强的抗肿瘤活性且能协同增强其他化疗药物的药效，但难溶于水，生物利用度低，限制了其在临床应用。本研究拟设计制备一种新型的两亲性和厚朴酚高分子-PEG键合物(PHK-PEG),其亲水部分由聚乙二醇(PEG)构成，疏水部分由HK与含有缩酮基团的三乙二醇二乙烯基醚单体通过缩合共聚制备的HK高分子（PHK）构成，可具有稳定的高载药量；PHK-PEG在水溶液中可自组装形成纳米胶束，被肿瘤细胞摄取后，可特异地在酸性溶酶体环境内水解并释放游离的HK。本项目拟系统研究PHK-PEG在水溶液的缔合行为、体外药物释放规律、体内药物代谢动力学，以及体内外抗肿瘤活性，探寻其结构与性能之间的相互关系，继而获得该类纳米药物结构与性能的调控方法，并从中优选出高性能的PHK-PEG作为药物载体用于化疗药物阿霉素的负载，以期通过药物间的协同作用，用于耐药肿瘤的治疗。

本项目通过缩合聚合反应合成两亲性聚合物PHK-PEG，其亲水部分由聚乙二醇(PEG)构成，疏水部分由HK与含有缩酮基团的三乙二醇二乙烯基醚单体通过缩合共聚制备的HK大分子（PHK）构成，载药量为21.2 %，且具有良好的批次重复性。PHK-PEG在水溶液中可自组装形成纳米胶束，被肿瘤细胞摄取后，可特异地在酸性溶酶体环境内水解并释放游离的HK；通过荧光共聚焦显微镜、MTT法和流式细胞分析技术对PHK-PEG的体外抗肿瘤活性进行了考察。结果表明，PHK-PEG在溶液中能够形成稳定的胶束分子，主要通过内吞途径被肿瘤细胞摄取，对Bcap-37、MCF-7、SKOV-3、MCF-7/ADR均显示出良好的抑制作用，以浓度依赖性的方式引起肿瘤细胞的凋亡，与同等浓度的HK相比，PHK-PEG对肿瘤细胞的凋亡作用更加显著；在此基础上，将PHK-PEG作为药物载体，用于阿霉素的负载，体内实验表明，PHK-PEG/DOX具有与DOX相当的抗肿瘤活性，但毒副作用更小。总之，PEK-PEG作为新型的高分子抗肿瘤药物，具有潜在的临床应用前景，值得进一步的深入研究。