Beijing National Laboratory for Molecular Sciences, CAS Key Laboratories of Organic Solids and State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, P. R. China.
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
Adv Mater. 2021 May;33(20):e2100599. doi: 10.1002/adma.202100599. Epub 2021 Apr 8.
A systematic combination strategy is proposed for overcoming cisplatin resistance using near-infrared (NIR)-light-triggered hyperthermia. A new photothermal polymer DAP-F is complexed with a reduction-sensitive amphiphilic polymer P1 to form F-NPs with photothermal effect. Subsequently, to build the final nanosystem F-Pt-NPs, F-NPs are combined with Pt-NPs, which are obtained by encapsulating a Pt(IV) prodrug with P1. Mild hyperthermia (43 °C), generated from F-Pt-NPs induced by an 808 nm NIR laser, have various effects such as: i) enhancing the cellular membrane permeability to promote the uptake of drugs; ii) activating cisplatin by accelerating the glutathione consumption; iii) increasing the Pt-DNA adducts formation and possibly the formation of a portion of irreparable Pt-DNA interstrand crosslinks, thereby inhibiting the repair of DNA. In vitro, it is found that even on cisplatin-resistant A549DDP cells, the IC of F-Pt-NPs (43 °C) is only 7.0 × 10 m Pt mL . In vivo, on a patient-derived xenograft model of multidrug resistant lung cancer, the efficacy of the F-Pt-NPs (43 °C) treatment group shows a tumor inhibition rate of 94%. Taken together, here, an important perspective of resolving cascade drug resistance with the assistance of mild hyperthermia triggered by NIR light is presented, which can be of great significance for clinic translation.
提出了一种系统的组合策略，以克服顺铂耐药性，使用近红外（NIR）光触发的热疗。一种新的光热聚合物 DAP-F 与还原敏感的两亲聚合物 P1 复合，形成具有光热效应的 F-NPs。随后，为了构建最终的纳米系统 F-Pt-NPs，将 F-NPs 与 Pt-NPs 结合，Pt-NPs 是通过用 P1 包裹 Pt(IV)前药而得到的。温和的热疗（43°C），由 808nm NIR 激光诱导的 F-Pt-NPs 产生，具有多种作用，例如：i）增强细胞膜通透性，促进药物摄取；ii）通过加速谷胱甘肽消耗来激活顺铂；iii）增加 Pt-DNA 加合物的形成，并可能形成一部分不可修复的 Pt-DNA 链间交联，从而抑制 DNA 的修复。在体外，即使在顺铂耐药的 A549DDP 细胞中，F-Pt-NPs（43°C）的 IC 也只有 7.0×10 m Pt mL 。在多药耐药肺癌的患者来源异种移植模型中，F-Pt-NPs（43°C）治疗组的疗效显示出 94%的肿瘤抑制率。总之，本文提出了一种利用 NIR 光触发的温和热疗来解决级联耐药性的重要观点，这对于临床转化具有重要意义。
