Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response <i>In Vivo</i>

Abstract

Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs <b>3</b>-<b>6</b>, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER⁺) cells, among which <b>3</b> presented the most potent cytotoxicity toward ER⁺ MCF-7 with nanomolar IC₅₀ values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, <b>3</b> evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, <b>3</b> effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin <i>in vivo</i>, promoting lymphocyte proliferation in spleen to achieve immune modulation.