Transferrin-Modified Carprofen Platinum(IV) Nanoparticles as Antimetastasis Agents with Tumor Targeting, Inflammation Inhibition, Epithelial–Mesenchymal Transition Suppression, and Immune Activation Properties,Journal of Medicinal Chemistry

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Transferrin-Modified Carprofen Platinum(IV) Nanoparticles as Antimetastasis Agents with Tumor Targeting, Inflammation Inhibition, Epithelial–Mesenchymal Transition Suppression, and Immune Activation Properties
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-05 , DOI: 10.1021/acs.jmedchem.4c01265
Ming Zhang ₁ , Yan Chen _{1,

2} , Shuaiqi Feng ₁ , Yanqin He ₁ , Zhifang Liu ₁ , Ning Zhang ₁ , Qingpeng Wang ₁

Affiliation

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@CPF₂–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 CPF₂–Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF₂–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.

中文翻译：

转铁蛋白修饰的卡洛芬铂（IV）纳米颗粒作为抗转移剂，具有肿瘤靶向、炎症抑制、上皮-间充质转化抑制和免疫激活特性

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，开发了转铁蛋白修饰的卡洛芬铂（IV）纳米颗粒 Tf-NPs@CPF_2-Pt（IV），具有很好的抗增殖和抗转移特性，除了引起 DNA 损伤外，还通过抑制炎症、抑制 EMT 和激活免疫反应来激活。纳米颗粒持续释放活性成分 CPF_2-Pt（IV），与体内游离 CPF_2-Pt（IV）相比，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作用。γ-H2AX 和 P53 的上调诱导了严重的 DNA 损伤，并启动了线粒体介导的凋亡途径 Bcl-2/Bax/caspase3。通过抑制 COX-2 和 MMP9 以及减少炎性细胞因子 TNF-α 和 IL-6 来缓解炎症。随后，通过抑制 Wnt/β-catenin 通路逆转 EMT。此外，通过阻断免疫检查点 PD-L1 和增加肿瘤中 CD3⁺ 和 CD8⁺ T 淋巴细胞来激发抗肿瘤免疫。

更新日期：2024-09-05

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