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

Autor: Zhang M; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China., Chen Y; 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., Feng S; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China., He Y; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China., Liu Z; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China., Zhang N; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China., Wang Q; Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng 252059, P. R. China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16416-16434. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1021/acs.jmedchem.4c01265
Abstrakt: 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 2 -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 2 -Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF 2 -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.
Databáze: MEDLINE