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.