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

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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.