Xue Kaihang, Wei Feng, Lin Jinyan, Tian Haina, Zhu Fukai, Li Yang, Hou Zhenqing
Department of Biomaterials, College of Materials, Research Center of Biomedical Engineering of Xiamen & Key Laboratory of Biomedical Engineering of Fujian Province, Xiamen University, Xiamen 361005, P. R. China.
Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361024, P. R. China.
Biomater Sci. 2021 Feb 9;9(3):1008-1019. doi: 10.1039/d0bm01864c.
Carrier-free nanodrugs composed of photosensitizers and chemotherapeutic drugs show great potential in synergistic photothermal-chemotherapy. However, the targeting specificity to tumor cells is still a major obstacle for carrier-free nanodrugs. Meanwhile, almost all exogenous tumor-targeting ligands show no therapeutic effect by themselves. Here, a tumor microenvironment-driven self-targeting supramolecular nanodrug was successfully constructed via an indocyanine green (ICG)-templated small-molecule self-assembly strategy with methotrexate (MTX, folic acid-like antitumor drug) followed by post-insertion of weak acidity-responsive PEG for synergistic photothermal-chemotherapy. Interestingly, the size and morphology could be adjusted by changing the ICG-to-MTX ratio. Notably, the dynamic introduction of PEG not only could temporarily shield self-targeting function in blood to prolong the circulation time, but also could trigger the activation of self-targeting via re-exposing MTX ligands within the tumor microenvironment to enhance cellular uptake. Furthermore, the dePEGylated nanodrug would be disassembled to release MTX on-demand for chemotherapy via both stimuli of stronger lysosomal acidity and an external NIR laser. Moreover, the elimination of tumors could be realized through NIR-II fluorescence/PA imaging-guided synergistic photothermal-chemotherapy. The tumor microenvironment-driven carrier-free nanodrug based on self-targeting activation via ICG-templated assembly might provide a brand-new idea for synergistic photothermal-chemotherapy.
由光敏剂和化疗药物组成的无载体纳米药物在光热化疗协同治疗中显示出巨大潜力。然而，对肿瘤细胞的靶向特异性仍然是无载体纳米药物的主要障碍。同时，几乎所有外源性肿瘤靶向配体自身都没有治疗效果。在此，通过吲哚菁绿（ICG）模板化的小分子自组装策略，以甲氨蝶呤（MTX，叶酸类抗肿瘤药物）为原料，随后后插入弱酸性响应性聚乙二醇（PEG），成功构建了一种肿瘤微环境驱动的自靶向超分子纳米药物，用于光热化疗协同治疗。有趣的是，尺寸和形态可以通过改变ICG与MTX的比例来调节。值得注意的是，PEG的动态引入不仅可以在血液中暂时屏蔽自靶向功能以延长循环时间，还可以通过在肿瘤微环境中重新暴露MTX配体来触发自靶向激活，从而增强细胞摄取。此外，去PEG化的纳米药物将通过更强的溶酶体酸度和外部近红外激光的双重刺激按需分解以释放MTX用于化疗。此外，通过近红外二区荧光/光声成像引导的光热化疗协同治疗可以实现肿瘤的消除。基于ICG模板化组装的自靶向激活的肿瘤微环境驱动的无载体纳米药物可能为光热化疗协同治疗提供全新思路。
