Search

Abstract Modification of platinum (II) into lipophilic platinum (IV) compounds by introducing biologically active molecules were widely employed to develop new platinum-based prodrugs in the past decade. In this paper, two chlorambucil platinum (IV) complexes, CLB-Pt and CLB-Pt-CLB, were synthesized and displayed very potent antiproliferative activity against all the tested cancer cell lines, such as A549, HeLa and MCF-7, especially to treat the well-known refractory triple-negative breast cancer. CLB-Pt-CLB significantly improved cell-killing effect in triple-negative subtype MDA-MB-231 cells, and showed much stronger cytotoxicity than either monotherapy or combination of cisplatin and chlorambucil. CLB-Pt-CLB prodrug entered cells in dramatically increased amount compared with cisplatin and enhanced DNA damage, inducing cancer cell apoptosis. It exhibited high anticancer activity and no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. The chlorambucil moiety not only greatly assisted the passive diffusion of CLB-Pt-CLB into cells, but also produced the synergism with cisplatin in targeting DNA. Graphical abstract Image 1 Highlights • Chlorambucil-conjugated platinum(IV) prodrugs increased therapeutic efficacy in triple-negative breast cancer cells. • The excellent anti-tumor effect was related to the synergy of chlorambucil and cisplatin. • CLB-Pt-CLB greatly enhanced cellular uptake and modified pharmacokinetic effects. • CLB-Pt-CLB enlarged DNA damage compared with cisplatin. • There was no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. [ABSTRACT FROM AUTHOR]