Fighting Against Cisplatin-Resistant Tumors Using Responsive Pt(IV)/Ru(II) Bimetallic Polymers

顺铂在全球范围内用于治疗人类癌症。耐药性使顺铂对患者无效，是癌症治疗中的一大问题。使用纳米载体输送顺铂可以部分解决这一问题。然而，传统的纳米载体无法避免导致顺铂耐药的一些失活途径。此外，纳米载体还受到其他失活途径的影响，例如内体捕获。因此，即使使用传统的纳米载体，顺铂的耐药性仍然是一个挑战。此外，肿瘤和健康细胞之间缺乏选择性是顺铂的另一个主要缺点。基于我们在用于抗癌光疗的多金属药物方面的合作(这是两位申请者的联合论文：Adv.Mater。2017年，29,1603702)，在这项提议中，我们计划合成铂(IV)/Ru(II)双金属聚合物聚乙二醇-b-P(铂/Ru)-b-聚乙二醇来治疗患者来源的异种移植(PDXs)小鼠模型中的顺铂耐药肿瘤。聚乙二醇单嵌段共聚物是一种可自组装成胶束的两亲性三嵌段共聚物。亲水性的聚乙二醇(PEG)阻止了胶束的血液循环。我们打算将聚乙二醇-b-P(铂/Ru)-b-聚乙二醇胶束静脉注射到对顺铂耐药的PC3肿瘤的小鼠模型中。胶束在肿瘤组织的聚集将通过增强的渗透性和滞留(EPR)效应实现。聚乙二醇块上的末端叶酸基团可以增强细胞对肿瘤组织中积累的胶束的摄取。为了帮助胶束通过内吞作用进入肿瘤细胞的细胞质，胶束将被红光照射产生1O2，它可以氧化内体，促进内体逃逸。在红光照射下，P(Pt/Ru)块中的Ru(II)部分能被迅速降解并产生10O2。此外，通过细胞内还原铂(IV)部分，可以进一步降解P(Pt/Ru)块。铂(IV)部分是一种前药，还原后释放顺铂。释放的铂和Ru络合物以及产生的1O2抑制肿瘤细胞的生长。由于双金属聚合物的设计是为了克服顺铂和传统纳米载体的失活途径，它为对抗耐药性提供了一种新的策略。此外，光触发的内体逃逸和快速降解只发生在受照射的肿瘤组织中，这进一步提高了治疗的选择性。两位申请者之前曾在一个相关项目上成功合作；他们独特的专业知识将分别贡献给拟议项目的化学和生物部分。因此，他们的合作是完成拟议项目的一种非常有价值和高效的方式。

Cisplatin is used worldwide for treating cancer in humans. Drug resistance, which makes cisplatin inefficient to patients, is a big problem in cancer treatment. The use of nano-carriers for cisplatin delivery can partially solve this problem. However, conventional nano-carriers cannot avoid some deactivation pathways that cause cisplatin resistance. Moreover, nano-carriers suffer from other deactivation pathways such as endosomal trapping. Therefore, cisplatin resistance remains a challenge even when conventional nano-carriers are used. In addition, the lack of selectivity between tumor and healthy cells is another major drawback for cisplatin.Based on our collaboration on polymetallodrugs for anticancer phototherapy (a joint paper by the two applicants: Adv. Mater. 2017, 29, 1603702), in this proposal, we plan to synthesize the Pt(IV)/Ru(II) bimetallic polymer PEG-b-P(Pt/Ru)-b-PEG to treat cisplatin-resistant tumors in a patient-derived xenografts (PDXs) mouse model. PEG-b-P(Pt/Ru)-b-PEG is an amphiphilic triblock copolymer that can self-assemble into micelles. The hydrophilic poly(ethylene glycol) (PEG) blocks prolong blood circulation of the micelles. We intend to intravenously inject the PEG-b-P(Pt/Ru)-b-PEG micelles into a mouse model that bears a cisplatin-resistant PC3 tumor. The accumulation of the micelles at the tumor tissue will be achieved via the enhanced permeability and retention (EPR) effect. The terminal folate groups on the PEG blocks can enhance cellular uptake of the accumulated micelles at the tumor tissue. To assist the micelles to enter the cytoplasm of the tumor cells via endocytosis, the micelles will be irradiated with red light to generate 1O2, which can oxidize endosomes and facilitates endosomal escape. The Ru(II) moieties in the P(Pt/Ru) block can be quickly degraded and generate 1O2 under red light irradiation. In addition, the P(Pt/Ru) block can be further degraded by intracellular reduction of the Pt(IV) moieties. The Pt(IV) moiety is a prodrug that releases cisplatin after reduction. The released Pt and Ru complexes as well as the generated 1O2 inhibit the growth of tumor cells. Because the design of the bimetallic polymer is to overcome the deactivation pathways for both cisplatin and conventional nano-carriers, it provides a new strategy to fight against drug resistance. Furthermore, light-triggered endosomal escape and quick degradation only occur at the irradiated tumor tissue, which further improve therapeutic selectivity.The two applicants previously had successful collaboration on a related project; their distinct expertise will be contributed to the chemistry and biology parts of the proposed project, respectively. Therefore, their collaboration is a highly valuable and efficient way to complete the proposed project.