Wang Chonggao, Cheng Xiaolan, Peng Hao, Zhang Yewei
Medical School, Southeast University, Nanjing, 210009, China.
Nanjing Hospital of Chinese Medicine, Nanjing, 210000, China.
Nanoscale Res Lett. 2022 Sep 20;17(1):92. doi: 10.1186/s11671-022-03729-w.
Although being the first-line treatment of advanced hepatocellular carcinoma (HCC), sorafenib (SOR) outcome is limited due to drug resistance and low tumor accumulation. Herein, with MnO as photothermal agent and chlorine6 (Ce6) as photosensitizer, a tumor-targeting and NIR-triggered multifunctional nanoplatform loading sorafenib (MnO-SOR-Ce6@PDA-PEG-FA, MSCPF) was constructed. Owing to oxygen generator MnO, MSCPF could generate excessive ROS, thus can alleviate tumor hypoxia and improve sorafenib accumulation in cancer cells. Besides, ROS production further strengthens Ce6-mediated PDT and PDA-mediated PTT. By exploiting these features, MSCPF exhibited excellent antitumor effects on HCC in the in vitro and in vivo studies, compared to solo sorafenib or PDT/PTT treatment. Further mechanism experiments suggested that MSCPF could inhibit P-gp expression and induce ferroptosis via deactivation of GPX4 and SLC7A11, which ultimately enhanced the antitumor efficacy of SOR. In summary, our work highlights a promising NIR-triggered and ROS-boosted nanoplatform for enhanced chemo/PDT/PTT synergistic therapy of SOR in HCC treatment.
尽管索拉非尼（SOR）是晚期肝细胞癌（HCC）的一线治疗药物，但由于耐药性和肿瘤蓄积率低，其治疗效果有限。在此，以MnO作为光热剂、氯6（Ce6）作为光敏剂，构建了一种负载索拉非尼的肿瘤靶向且近红外触发的多功能纳米平台（MnO-SOR-Ce6@PDA-PEG-FA，MSCPF）。由于氧气生成剂MnO，MSCPF能够产生过量的活性氧（ROS），从而缓解肿瘤缺氧并提高索拉非尼在癌细胞中的蓄积。此外，ROS的产生进一步增强了Ce6介导的光动力疗法（PDT）和聚多巴胺（PDA）介导的光热疗法（PTT）。利用这些特性，与单独使用索拉非尼或PDT/PTT治疗相比，MSCPF在体外和体内研究中均对HCC表现出优异的抗肿瘤效果。进一步的机制实验表明，MSCPF可抑制P-糖蛋白（P-gp）表达，并通过使谷胱甘肽过氧化物酶4（GPX4）和溶质载体家族7成员11（SLC7A11）失活诱导铁死亡，最终增强了索拉非尼的抗肿瘤疗效。总之，我们的工作突出了一种有前景的近红外触发且ROS增强的纳米平台，用于增强索拉非尼在HCC治疗中的化学疗法/PDT/PTT协同治疗。
