Abstract

Design of Pt(IV) prodrugs with biologically active axial ligands is an excellent approach to overcome the disadvantages (nonspecific killing, side effects, and drug resistance) of conventional first-line Pt(II)-based chemotherapeutic drugs, such as cisplatin, carboplatin and oxaliplatin. The selection of ideal axial ligands is essential for the success of Pt(IV) drugs. Previously, that berberine exhibits great superiority in tumor selectivity is found with uncovered mechanisms. In this study, that berberine is specifically internalized and accumulated in tumors but not normal cells through endocytosis pathways is first disclosed. Therefore a new Pt(IV) prodrug of cisplatin bearing berberine as an axial ligand, named berplatin, is designed and synthesized. Different from cisplatin, berplatin can be effectively and selectively internalized into cancer cells, through macropinocytosis and caveolin-1 (CAV-1)-dependent active endocytosis, and cleaved in intracellular reductive environments to generate cisplatin and berberine, which synergistically induces substantial DNA breaking, apoptosis and cell cycle arrest in both cisplatin-sensitive and -resistant cancer cells. In vivo, berplatin manifests much higher antitumor activity and undetectable side effects compared to cisplatin. This study demonstrates that berplatin can serve as a potent Pt(IV) prodrug for the treatment of cisplatin-sensitive and -resistant cancers with active uptake, excellent specificity, and minimal side effects.