Multi-specific niflumic acid platinum(IV) complexes displaying potent antitumor activities by improving immunity and suppressing angiogenesis besides causing DNA damage

To develop new chemotherapeutics with anti-metastasis properties, a series of multi-specific niflumic acid (NFA) platinum(IV) complexes with DNA damage, inflammation inhibition, immunity activation, and angiogenesis suppression mechanisms were designed, synthesized and evaluated as novel antitumor agents. The dual NFA platinum(IV) complex with a cisplatin core showed promising antitumor activities both in vitro and in vivo with lower toxicity than platinum(II) drugs and displayed attractive anti-metastasis performance. It caused serious DNA damage and further elevated the expression of γ-H2AX. Furthermore, it promoted apoptosis by activating the mitochondrial apoptotic pathway and autophagy of tumor cells. Moreover, immune response in tumors was significantly improved by increasing CD3+, CD4+ and CD8+ T infiltrating cells. Subsequently, the pathway ERK/HIF-1α/VEGFA associated with angiogenesis was suppressed by the reduced inflammation and elevated immune response, and the density of microvessels marked by CD34 was significantly reduced in tumors. Accordingly, the multi-specific NFA platinum(IV) complexes have great potential to be developed as novel anti-proliferative and anti-metastatic drugs.