MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, People's Republic of China.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China.
ACS Nano. 2021 May 25;15(5):8663-8675. doi: 10.1021/acsnano.1c00698. Epub 2021 Apr 30.
The development of a controllable reactive nitrogen species (RNS) generation system for cancer treatment has remained elusive. Herein, a supramolecular prodrug nanoassemblies (SPNA) strategy that co-delivers a nitric oxide (NO) donor and a superoxide anion (O) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor could be precisely tailored in SPNA. Platinum(II) and NO would be released intracellularly to produce a highly toxic RNS, peroxynitrite anion (ONOO). The levels of glutathione reductase (GR) and xeroderma pigmentosum group A (XPA) were down-regulated by ONOO, thus synergistically decreasing detoxification and blocking DNA damage repair of Pt-based chemotherapy. The RNS-potentiated efficacy of SPNA was validated on subcutaneous hepatoma xenograft models and an orthotopic cisplatin-resistant hepatoma model. This co-delivery strategy of NO donor and O inducing chemotherapeutic agents for RNS-mediated therapy provides an insightful direction for cancer treatment.
用于癌症治疗的可控活性氮物种 (RNS) 生成系统的开发一直难以实现。在此，报道了一种超分子前药纳米组装体 (SPNA) 策略，该策略同时递送一氧化氮 (NO) 供体和超氧阴离子 (O) 诱导化疗药物，以增强 RNS 化疗。SPNA 中铂 (IV) 前药和 NO 供体的摩尔比可以精确调整。铂 (II) 和 NO 会在细胞内释放，产生高度毒性的 RNS，过氧亚硝酸盐阴离子 (ONOO)。ONOO 下调谷胱甘肽还原酶 (GR) 和着色性干皮病 A 组 (XPA) 的水平，从而协同降低基于铂的化疗的解毒和阻断 DNA 损伤修复。SPNA 的 RNS 增强功效在皮下肝癌异种移植模型和原位顺铂耐药肝癌模型中得到了验证。这种 NO 供体和 O 诱导化疗药物的共递送策略为 RNS 介导的治疗提供了一个有见地的癌症治疗方向。
