Ketoprofen and Loxoprofen Platinum(IV) Complexes Displaying Antimetastatic Activities by Inducing DNA Damage, Inflammation Suppression, and Enhanced Immune Response

Metastasis is a major contributor of death in cancer patients, and there is an urgent need for effective treatments of metastatic malignancies. Herein, ketoprofen (KP) and loxoprofen (LP) platinum­(IV) complexes with antiproliferative and antimetastatic properties were designed and prepared by integrating chemotherapy and immunotherapy targeting cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and programmed death ligand 1 (PD-L1), besides DNA. A mono-KP platinum­(IV) complex with a cisplatin core is screened out as a candidate possessing potent anti-proliferative and anti-metastasis activities both in vitro and in vivo. It induces serious DNA damage and further leads to high expression of γ-H2AX and p53. Moreover, it promotes apoptosis of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3. Then, COX-2, MMP-9, NLRP3, and caspase1 as pivotal enzymes igniting inflammation and metastasis are obviously inhibited. Notably, it significantly improves immune response through restraining the expression of PD-L1 to increase CD3 + and CD8 + T infiltrating cells in tumor tissues.