Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer
Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer
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DOI：
10.1002/adma.202004766
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发表时间：
2020-09
影响因子：
29.4
通讯作者：
Xiaolong Zeng;Yufei Wang;Jianxiong Han;Wen Sun;H. Butt;Xing-jie Liang;Si Wu
中科院分区：
文献类型：
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作者：
Xiaolong Zeng;Yufei Wang;Jianxiong Han;Wen Sun;H. Butt;Xing-jie Liang;Si Wu
耐药性是癌症治疗中的主要问题。本文中，报道了在患者来源的异种移植物（PDX）模型中治疗顺铂抗性肿瘤的双重响应Pt（IV）/Ru（II）双链聚合物（PolyPt/Ru）的设计。PolyPt/Ru是一种两亲性阿坝-型三嵌段共聚物。亲水性A嵌段由生物相容性聚（乙二醇）（PEG）组成。疏水性B嵌段含有还原响应性Pt（IV）和红光响应性Ru（II）部分。PolyPt/Ru自组装成纳米颗粒，被顺铂耐药癌细胞有效吸收。用红光照射含有PolyPt/Ru纳米颗粒的癌细胞会产生1 O2，诱导聚合物降解，并引发Ru（II）抗癌剂的释放。同时，抗癌药物顺铂通过Pt（IV）部分的还原在细胞内环境中释放。释放的Ru（II）抗癌剂顺铂和产生的1 O2具有不同的抗癌机制;它们的协同效应抑制耐药癌细胞的生长。此外，PolyPt/Ru纳米颗粒在PDX小鼠模型中抑制肿瘤生长，因为它们在血流中循环，在肿瘤部位积聚，表现出良好的生物相容性，并且不会引起副作用。结果表明，刺激响应性多金属聚合物的发展为克服耐药性提供了一种新的策略。
Drug resistance is a major problem in cancer treatment. Herein, the design of a dual‐responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin‐resistant tumors in a patient‐derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA‐type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction‐responsive Pt(IV) and red‐light‐responsive Ru(II) moieties. PolyPt/Ru self‐assembles into nanoparticles that are efficiently taken up by cisplatin‐resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1O2, induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug‐resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli‐responsive multi‐metallic polymers provides a new strategy to overcome drug resistance.