Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
Sci Adv. 2023 Mar 29;9(13):eadf6854. doi: 10.1126/sciadv.adf6854.
Immune checkpoint inhibitors (ICIs) can reinvigorate T cells to eradicate tumor cells, showing great potential in combating various types of tumors. We propose a delivery strategy to enhance tumor-selective ICI accumulation, which leverages the responsiveness of platelets and platelet-derivatives to coagulation cascade signals. A fused protein tTF-RGD targets tumor angiogenic blood vessel endothelial cells and initiates the coagulation locoregionally at the tumor site, forming a "cellular hive" to recruit anti-PD-1 antibody (aPD-1)-conjugated platelets to the tumor site and subsequently activating platelets to release aPD-1 antibody to reactivate T cells for improved immunotherapy. Moreover, on a patient-derived xenograft breast cancer model, the platelet membrane-coated nanoparticles can also respond to the coagulation signals initiated by tTF-RGD, thus enhancing the accumulation and antitumor efficacy of the loaded chemotherapeutics. Our study illustrates a versatile platform technology to enhance the local accumulation of ICIs and chemodrugs by taking advantage of the responsiveness of platelets and platelet derivatives to thrombosis.
免疫检查点抑制剂 (ICIs) 可以激活 T 细胞来消灭肿瘤细胞，在治疗各种类型的肿瘤方面具有巨大的潜力。我们提出了一种输送策略来增强肿瘤选择性 ICI 的积累，该策略利用了血小板和血小板衍生物对凝血级联信号的反应性。融合蛋白 tTF-RGD 靶向肿瘤血管生成的血管内皮细胞，并在肿瘤部位局部引发凝血，形成“细胞蜂巢”，将结合 PD-1 抗体 (aPD-1) 的血小板募集到肿瘤部位，随后激活血小板释放 aPD-1 抗体，重新激活 T 细胞以改善免疫治疗。此外，在患者来源的异种移植乳腺癌模型中，血小板膜包被的纳米颗粒也可以响应 tTF-RGD 引发的凝血信号，从而增强载药化疗药物的积累和抗肿瘤功效。我们的研究说明了一种利用血小板和血小板衍生物对血栓形成的反应性来增强 ICI 和化疗药物局部积累的多功能平台技术。
