Near-Infrared II Light-Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors
Near-Infrared II Light-Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors
复制标题
近红外 II 光触发稳健碳自由基生成，用于缺氧肿瘤的光热和热力学联合治疗
DOI：
10.1002/adfm.202101709
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发表时间：
2021-04-02
影响因子：
19
通讯作者：
Liu, Xiqiang
中科院分区：
文献类型：
--
作者：
Liu, Xin;Yang, Yuanyuan;Liu, Xiqiang
肿瘤缺氧是癌症治疗失败的主要原因，并且几乎没有针对缺氧肿瘤的有效治疗。本文中，含偶氮聚合物（P2）被设计成包封IR 1061，并进一步与肿瘤靶向三肽RGD共价接枝以形成P2@IR 1061-RGD NP，用于在近红外II（NIR II）生物窗口（1000-1700 nm）中的组合光热和热力学疗法（PTT/TDT）。在1064 nm激光照射下，IR 1061产生热量以破坏P2的偶氮键，实现稳健的碳自由基产生，即使在缺氧肿瘤微环境下也能诱导癌细胞死亡。首次采用RNA测序来揭示组合PTT/TDT对细胞转录组的影响以及使用4 T1乳腺癌细胞的相应途径。这些失调的基因参与内质网内的蛋白质加工、细胞周期调节、泛素介导的蛋白水解和DNA复制途径。在4 T1乳腺癌模型以及肝细胞癌的患者来源的异种移植物模型（PDXHCC）上的肿瘤抑制率为97%和100%，并且观察到可忽略的全身毒性。本研究提出了一种含偶氮聚合物的应用，用于NIR II biowindow中安全有效的组合PTT/TDT，作为临床治疗缺氧肿瘤的一种有前途的策略。
Tumor hypoxia is a major cause of failure in cancer therapy, and there is almost no efficacious treatment for hypoxic tumors. Herein, an azo-containing polymer (P2) is designed to encapsulate IR1061, and further covalently grafted with a tumor-targeting tripeptide RGD to form P2@IR1061-RGD NPs for combined photothermal and thermodynamic therapy (PTT/TDT) in the near-infrared II (NIR II) biowindow (1000-1700 nm). Upon 1064 nm laser irradiation, IR1061 generates heat to break the azo bonds of P2, achieving robust carbon radical generation, which induces cancer cell death even under a hypoxic tumor microenvironment. RNA-sequencing is first adopted to unveil the impact of combined PTT/TDT on the cell transcriptome and the corresponding pathways using 4T1 breast cancer cells. The dysregulated genes are involved in protein processing within the endoplasmic reticulum, cell cycle regulation, ubiquitin-mediated proteolysis, and DNA replication pathways. The tumor inhibition rates on a 4T1 breast cancer model as well as on a patient-derived xenograft model of hepatocellular carcinoma (PDXHCC) are 97% and 100%, and negligible systematic toxicity is observed. This study proposes the application of an azo-containing polymer for safe and efficient combined PTT/TDT in the NIR II biowindow, as a promising strategy for clinical treatment of hypoxic tumors.