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

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.