Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology, and Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
ACS Appl Mater Interfaces. 2021 Mar 24;13(11):12845-12856. doi: 10.1021/acsami.0c20422. Epub 2021 Mar 12.
Tumor immunotherapy like immune checkpoint blockade (ICB) shows great success nowadays but is severely limited by low response rates and immune-related adverse events (IRAEs). While photodynamic therapy (PDT) could efficiently eradicate tumor cells and further induce immune responses to promote activating of T lymphocytes. Herein a nanodrug hierarchically incorporating photosensitizer and PD-L1 antibody was developed for synergistic tumor immuno-photodynamic therapy. A pH/enzyme dual-sensitive polymeric micelle with sheddable PEG coating was designed for codelivery of PD-L1 antibody and zinc phthalocyanine (ZnPc) in the tumor. The tumor microenvironment featuring low pH and high matrix metallopeptidase 2 (MMP-2) sequentially triggered the shedding of PEG and the release of PD-L1 antibody to exert local ICB in tumor tissue, after which the remaining nanodrug with ZnPc undergoing charge reversal was readily delivered into tumor cells. With light irradiation, the photodynamic therapy effect of sAMPc induced immunogenic cell death of tumor cells and further promoted intratumor recruitment of CD8+ T cells, thus resulting in a synergistic immuno-photodynamic therapy with ICB. Moreover, the PEG-sheddable strategy endowed the nanodrug with stealth properties in blood circulation, making the IRAEs of PD-L1 antibody significantly reduced. This pH/MMP-2 dual-sensitive PEG sheddable nanodrug provids a promising strategy for well-combined ICB therapy and PDT to achieve improved anticancer immuno-photodynamic therapy with reduced adverse effects.
肿瘤免疫疗法，如免疫检查点阻断（ICB），如今取得了巨大的成功，但由于响应率低和免疫相关不良反应（IRAEs）而受到严重限制。而光动力疗法（PDT）可以有效地消灭肿瘤细胞，并进一步诱导免疫反应，促进 T 淋巴细胞的激活。在此，我们开发了一种纳米药物，将光敏剂和 PD-L1 抗体进行了层级整合，用于协同肿瘤免疫光动力治疗。设计了一种具有可脱落聚乙二醇（PEG）涂层的 pH/酶双重敏感聚合物胶束，用于共递送 PD-L1 抗体和锌酞菁（ZnPc）进入肿瘤。肿瘤微环境具有低 pH 值和高基质金属蛋白酶 2（MMP-2）的特点，可依次触发 PEG 的脱落和 PD-L1 抗体的释放，在肿瘤组织中发挥局部 ICB，然后剩余的带 ZnPc 的纳米药物发生电荷反转，容易进入肿瘤细胞。光照后，sAMPc 的光动力治疗效应诱导肿瘤细胞发生免疫原性细胞死亡，并进一步促进 CD8+T 细胞在肿瘤内的募集，从而实现具有 ICB 的协同免疫光动力治疗。此外，PEG 可脱落策略使纳米药物在血液循环中具有隐身特性，显著降低了 PD-L1 抗体的 IRAEs。这种 pH/MMP-2 双重敏感的 PEG 可脱落纳米药物为联合 ICB 治疗和 PDT 提供了一种有前途的策略，可实现具有降低不良反应的改良抗癌免疫光动力治疗。
