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

顺铂在世界范围内用于治疗人类癌症。耐药性是癌症治疗中的一个大问题，它使顺铂对患者无效。使用纳米载体进行顺铂递送可以部分解决这一问题。然而，传统的纳米载体无法避免一些导致顺铂耐药的失活途径。此外，纳米载体遭受其他失活途径，如内体捕获。因此，即使使用传统的纳米载体，顺铂耐药性仍然是一个挑战。此外，肿瘤细胞和健康细胞之间缺乏选择性是顺铂的另一个主要缺点。基于我们在多金属药物抗癌光疗方面的合作（两位申请人的联合论文：ad . Mater. 2017,29,1603702），在本提案中，我们计划合成Pt(IV)/Ru（II）双金属聚合物PEG-b-P(Pt/Ru)-b-PEG，用于治疗患者源性异种移植（PDXs）小鼠模型中的顺铂耐药肿瘤。PEG-b-P(Pt/Ru)-b-PEG是一种可自组装成胶束的两亲性三嵌段共聚物。亲水性聚乙二醇（PEG）阻滞延长了胶束的血液循环。我们打算将PEG-b-P(Pt/Ru)-b-PEG胶束静脉注射到具有顺铂耐药PC3肿瘤的小鼠模型中。胶束在肿瘤组织的积累将通过增强的渗透性和保留（EPR）效应来实现。聚乙二醇块上的末端叶酸基团可以增强肿瘤组织中积聚的胶束的细胞摄取。为了帮助胶束通过内吞作用进入肿瘤细胞的细胞质，红光照射胶束产生1O2，氧化核内体，促进核内体逃逸。在红光照射下，P（Pt/Ru）区块中的Ru（II）基团可以快速降解并生成1O2。此外，P（Pt/Ru）阻滞可以通过细胞内Pt（IV）部分的还原进一步降解。铂（IV）部分是前药，还原后释放顺铂。释放的Pt和Ru复合物以及产生的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仅发生在照射的肿瘤组织中，这进一步提高了治疗的选择性。两名申请人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有效的方式。

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.