In Vivo-assembled phthalocyanine/albumin supramolecular complexes combined with a hypoxia-activated prodrug for enhanced photodynamic immunotherapy of cancer
In Vivo-assembled phthalocyanine/albumin supramolecular complexes combined with a hypoxia-activated prodrug for enhanced photodynamic immunotherapy of cancer
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DOI：
10.1016/j.biomaterials.2020.120430
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发表时间：
2021-01-01
期刊：
影响因子：
14
通讯作者：
Yoon, Juyoung
中科院分区：
文献类型：
--
作者：
Li, Xingshu;Jeon, Yun-Hui;Yoon, Juyoung
免疫原性光动力疗法（PDT）有可能弥补癌症免疫疗法的不足。然而，由于缺乏最佳光敏剂和智能递送过程以及PDT固有的缺点（例如，耐缺氧性），其功效受到严重限制。在这里，我们展示了一种具有临床前景的方法，即利用水溶性酞菁衍生物（PcN4）与缺氧激活的前药（AQ4N）一起递送，以增强PDT的效果并增强癌症免疫治疗。经静脉注射后，PcN4选择性地与内源性白蛋白二聚体相互作用，形成超分子复合物，为肿瘤靶向PDT提供了一种便捷、绿色的途径。同时给药AQ4N克服了PDT缺氧的局限性，提高了PDT的抗肿瘤活性。在三阴性乳腺癌模型中，pcn4介导和aq4n扩增的PDT治疗几乎完全根除了相当大的原发性肿瘤，并显著激活了CD8(+) T细胞。由于大多数肿瘤浸润性CD8(+) T细胞都是PD-1-和tim3阳性，因此需要使用PD-L1/PD-1通路阻断的额外联合治疗。在联合免疫检查点阻断治疗后，在远处和转移性肿瘤中均实现了增强的体外效应。
Immunogenic photodynamic therapy (PDT) has the potential to moderate the shortfalls of cancer immunotherapy. However, its efficacy is severely limited particularly because of the lack of optimal photosensitizers and smart delivery processes and the inherent shortcomings of PDT (e.g., hypoxia resistance). Here, we demonstrate a clinically promising approach that utilizes a water-soluble phthalocyanine derivative (PcN4) concomitantly delivered with a hypoxia-activated prodrug (AQ4N) to amplify the effect of PDT and enhance cancer immunotherapy. After intravenous injection, PcN4 selectively interacted with endogenous albumin dimers and formed supramolecular complexes, providing a facile and green approach for tumor-targeted PDT. The concomitant delivery of AQ4N overcame the limitations of hypoxia in PDT and improved the antitumor activity of PDT. Treatment with PcN4-mediated and AQ4N-amplified PDT almost completely eradicated sizable primary tumors in a triple-negative breast cancer model and significantly activated CD8(+) T cells. As the majority of tumor infiltrating CD8(+) T cells were both PD-1- and TIM3-positive, additional combination therapy using PD-L1/PD-1 pathway blockade was warranted. After combination with immune checkpoint blockade treatment, an enhanced abscopal effect was achieved in both distant and metastatic tumors.