用于肿瘤光热/分子靶向双向协同治疗的聚合物胶束研究

It is a major challenge to achieve highly efficient anticancer efficacy for cancer therapy. The nanoparticles with synergistic anticancer efficacy are considered as a new promising focus in this field. In this application, we propose to synthesize poly(ethylene glycol)-b-poly(L-cysteine)-b-poly(L- aspartic acid) triblock copolymer, and then develop pH-responsive core-cross-linked polymeric micelles with the bidirectional synergistic effects of photothermal and molecularly targeted therapies, in which photothermal Cypate is cross-linked within poly(L-aspartic acid) segment as inner hydrophobic cores, and 17-(Allylamino) -17-demethoxygeldanamycin (17-AAG)， a heat shock protein 90 (HSP90) inhibitor is also encapsulated within poly(L-cysteine)segment as exterior hydrophobic cores.The physicochemical properties of the micelles are optimized to achieve effective cancer targeting effect and enhanced cellular uptake.The pH-responsive micelles can induce the enhanced release of 17-AAG in response to lysosomal environment, aviod the release of Cypate from the micelles owing to the cross-linked cores and thus improve the photostability of Cypate. Meanwhile, Cypate within the micellar cores causes remarkable photothermal therapy upon photoirradiation and also induce the disruption of lysosomes, which facilitates the translocation of 17-AAG into cytoplasm and thus enhances the cyototxicity of 17-AAG against tumor cells via the highly effective interaction with HSP90. Moreover, 17-AAG is able to inhibit the ability of HSP90 to repair the photothermal damage and therefore improve the photothermal therapy of Cypate in return. This work is highly valuable to explore efficient anticancer formulation with low adverse side effect and novel synergistic strategy for cancer therapy as well.

肿瘤的高效治疗是肿瘤治疗领域的难点，构建具有肿瘤协同治疗效应的纳米粒是该领域的新方向。本项目拟合成聚乙二醇-b-聚半胱氨酸-b-聚天冬氨酸聚合物，通过光热治疗药物Cypate与聚天冬氨酸侧链的交联形成胶束疏水内核，在聚半胱氨酸侧链引入pH响应基团，形成胶束疏水外核，并包载热休克蛋白90(HSP90)抑制剂17-AAG，构建出具有光热、分子靶向治疗双向协同效应的载药胶束。通过调控胶束的理化特征，增强其肿瘤靶向、细胞摄取能力；胶束进入溶酶体后响应释放17-AAG，而通过交联作用避免Cypate的释放，增强其光稳定性；在光激发下胶束中Cypate产生显著的光热治疗作用，同时诱导溶酶体破裂，促进17-AAG的胞浆分布以及与HSP90的结合，增强其分子靶向治疗作用，并降低细胞热损伤修复能力，从而反向增强光热治疗效果。本项目对探索高效、低毒的抗肿瘤制剂以及新的协同治疗策略具有重要理论意义和实用价值。

课题负责人制备了载药聚合物纳米粒，增强药物的光热治疗作用，并提高了药物的胞内递送能力，发展出高效的肿瘤热疗与分子靶向治疗的协同治疗策略。纳米粒在胞内释放药物，并通过碳菁染料产生的活性氧自由基（ROS）破坏溶酶体促进胞浆转运，从而增强分子靶向药物如17AAG的分子靶向治疗效应；同时，分子靶向药物17AAG明显抑制了肿瘤细胞受热应激性过表达的热休克蛋白90，从而降低细胞的热耐受性，进而增强了碳菁染料光热效应对肿瘤细胞的光热损伤作用。这种双向协同增效通过更强的细胞凋亡和坏死效应，显著提升了纳米粒对肿瘤细胞的协同治疗效应，实现了肿瘤的消融。在项目的支持下，课题负责人作为通讯作者在Adv Mater、ACS Nano、Adv Funct Mater等高水平国际期刊发表SCI论文13篇，其中影响因子大于10的论文12篇，项目编号第一标注论文3篇；获授权中国发明专利3项。