Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China.
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China.
J Med Chem. 2024 Sep 26;67(18):16416-16434. doi: 10.1021/acs.jmedchem.4c01265. Epub 2024 Sep 5.
The inflammatory microenvironment is a central driver of tumor metastasis, intimately associated with the promotion of epithelial-mesenchymal transition (EMT) and immune suppression. Here, transferrin-modified carprofen platinum(IV) nanoparticles Tf-NPs@CPF-Pt(IV) with promising antiproliferative and antimetastatic properties were developed, which activated by inhibiting inflammation, suppressing EMT, and activating immune responses besides causing DNA injury. The nanoparticles released the active ingredient CPF-Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF-Pt(IV) in vivo. Additionally, they possessed satisfactory tumor targeting effects via the transferrin motif. Serious DNA damage was induced with the upregulation of γ-H2AX and P53, and the mitochondria-mediated apoptotic pathway Bcl-2/Bax/caspase3 was initiated. Inflammation was alleviated by inhibiting COX-2 and MMP9 and decreasing inflammatory cytokines TNF-α and IL-6. Subsequently, the EMT was reversed by inhibiting the Wnt/β-catenin pathway. Furthermore, the antitumor immunity was provoked by blocking the immune checkpoint PD-L1 and increasing CD3 and CD8 T lymphocytes in tumors.
炎症微环境是肿瘤转移的核心驱动因素，与促进上皮-间充质转化 (EMT) 和免疫抑制密切相关。在这里，开发了具有有前景的抗增殖和抗转移特性的转铁蛋白修饰的卡洛芬铂(IV)纳米颗粒 Tf-NPs@CPF-Pt(IV)，除了引起 DNA 损伤外，它还通过抑制炎症、抑制 EMT 和激活免疫反应来激活。与体内游离 CPF-Pt(IV) 相比，纳米颗粒以持续的方式释放有效成分 CPF-Pt(IV)，并具有增强的药代动力学特性。此外，它们通过转铁蛋白基序具有令人满意的肿瘤靶向效果。通过上调 γ-H2AX 和 P53 诱导严重的 DNA 损伤，并启动线粒体介导的凋亡途径 Bcl-2/Bax/caspase3。通过抑制 COX-2 和 MMP9 以及降低炎症细胞因子 TNF-α 和 IL-6 来减轻炎症。随后，通过阻断免疫检查点 PD-L1 并增加肿瘤中的 CD3 和 CD8 T 淋巴细胞来逆转 EMT。
