State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing 210093, China.
Department of Urology, Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210093, China.
ACS Nano. 2023 Aug 22;17(16):15388-15400. doi: 10.1021/acsnano.3c00295. Epub 2023 Aug 1.
Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-β (TGFβ) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFβ, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFβ. Therefore, downregulation of platelet-derived TGFβ is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFβ and in blood plasma. PFTBA@HSA-mediated TGFβ downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFβ, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFβ by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.
肿瘤转移导致肿瘤患者的总体生存率降低，而转化生长因子-β（TGFβ）已被认为是肿瘤转移发展的重要促进因素。血小板储备有丰富的 TGFβ，在激活后会被分泌到外周血中，是循环 TGFβ的主要来源。因此，下调血小板衍生的 TGFβ有望抑制循环肿瘤细胞的转移。在这里，构建了未折叠的人血清白蛋白（HSA）包裹的全氟三丁胺（PFTBA）纳米颗粒，以显示出良好的血小板传递能力和抗血小板作用，从而下调血小板衍生的 TGFβ，并在血浆中。PFTBA@HSA 介导的 TGFβ下调破坏了肿瘤细胞的上皮-间充质转化以及它们的迁移和侵袭行为，并增强了 NK 细胞的免疫监视。静脉注射 PFTBA@HSA 可有效减少肺部或肝脏的肿瘤转移，从而提高多种转移性模型（包括 CT26 结肠癌、B16F10 黑色素瘤和 4T1 乳腺癌）中小鼠的存活率。与临床抗血小板药物替卡格雷洛相比，PFTBA@HSA 在下调血小板衍生的 TGFβ方面降低了出血风险，从而获得了更高的治疗效益。综上所述，本研究证实了 PFTBA@HSA 下调血小板衍生的 TGFβ将是预防肿瘤转移的一种有潜力的方法和治疗候选物。
