Development of Ciprofibrate Platinum(IV) Nanodrugs as Antimetastatic Agents with COFs as Carriers

Dysregulated cholesterol accumulation promotes tumor growth and metastasis. Herein, a series of ciprofibrate platinum(IV) conjugates with cholesterol-inhibiting effects was developed, and the transferrin-modified nanodrug Tf-PEG-COFs@Pt(IV) was prepared using COFs as the carrier. The nanodrug exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. The transferrin moiety significantly enhanced the tumor-targeting ability of the nanodrug. The platinum core induced serious DNA damage, leading to an increased expression of γ-H2AX and p53. Mitochondria-mediated apoptosis occurred via the Bcl-2/Bax/caspase-3 cascade. Notably, cholesterol accumulation was inhibited by the ciprofibrate ligand through promoting PPAR-α expression and further regulating the LDLR/ACAT1/ABCA1 signaling. The nanodrug effectively reversed the epithelial-mesenchymal transition by inhibiting the PI3K/AKT/mTOR pathway and reversing the hypoxic microenvironment. Furthermore, antitumor immunity was enhanced by elevating the density of CD3⁺ and CD8⁺ T cells and triggering macrophage polarization from the M2 to M1 phenotype in tumors.