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

使用响应性 Pt(IV)/Ru(II) 双金属聚合物对抗顺铂耐药肿瘤

• 批准号: 392048923
• 负责人: Professor Dr. Hans-Jürgen Butt, since 12/2018
• 金额: --
• 依托单位: Max-Planck-Institut für Polymerforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392048923?language=en
• 关键词: Fighting; Against; Cisplatin; Resistant; Tumors

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.

顺铂在世界范围内用于治疗人类癌症。使顺铂对患者无效的耐药性是癌症治疗中的一个大问题。使用纳米载体进行顺铂递送可以部分解决这个问题。然而，传统的纳米载体不能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，即使使用常规纳米载体，顺铂抗性仍然是一个挑战。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。基于我们在抗癌光疗的多金属药物方面的合作（两个申请人的联合论文：Adv. Mater. 2017，29，1603702），在该提案中，我们计划合成Pt（IV）/Ru（II）双链聚合物PEG-b-P（Pt/Ru）-b-PEG，以治疗患者来源的异种移植物（PDX）小鼠模型中的顺铂耐药肿瘤。PEG-b-P（Pt/Ru）-b-PEG是一种两亲性的三嵌段共聚物，可以自组装成胶束。亲水性的聚乙二醇（PEG）阻断了胶束的血液循环。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PC 3肿瘤的小鼠模型中。胶束在肿瘤组织中的积累将通过增强的渗透性和保留（EPR）效应来实现。PEG嵌段上的末端叶酸基团可以增强肿瘤组织处累积胶束的细胞摄取。为了帮助胶束通过内吞作用进入肿瘤细胞的细胞质，将用红光照射胶束以产生1 O2，其可以氧化内体并促进内体逃逸。P（Pt/Ru）块中的Ru（II）部分在红光照射下可迅速降解并产生1 O2。此外，P（Pt/Ru）嵌段可通过Pt（IV）部分的细胞内还原而进一步降解。Pt（IV）部分是在还原后释放顺铂的前药。释放的Pt和Ru络合物以及产生的1 O2抑制肿瘤细胞的生长。由于顺铂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，因此它提供了一种对抗耐药性的新策略。此外，光引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。两个申请人之前在相关项目上进行了成功的合作;他们独特的专业知识将分别贡献于拟议项目的化学和生物学部分。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。

项目成果

Long Alkyl Side Chains Simultaneously Improve Mechanical Robustness and Healing Ability of a Photoswitchable Polymer

长烷基侧链同时提高光开关聚合物的机械鲁棒性和愈合能力

• DOI: 10.1021/acs.macromol.0c01784
• 发表时间: 2020-09
• 期刊: Macromolecules
• 影响因子: 5.5
• 作者: 张振琳

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

• DOI: 10.1002/adfm.201804227
• 发表时间: 2018-08
• 期刊: Advanced Functional Materials
• 影响因子: 19
• 作者: Wen Sun;Yan Wen;R. Thiramanas;Mingjia Chen;Jianxiong Han;N. Gong;M. Wagner;Shuai Jiang

Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer

• DOI: 10.1002/adma.202004766
• 发表时间: 2020-09
• 期刊: Advanced Materials
• 影响因子: 29.4
• 作者: Xiaolong Zeng;Yufei Wang;Jianxiong Han;Wen Sun;H. Butt;Xing-jie Liang;Si Wu