Multi-Functional Biotinylated Platinum(IV)-SAHA Conjugate for Tumor-Targeted Chemotherapy

Abstract

The development of multi-functional metal-based chemotherapeutic agents have gained growing attention in medical oncology. Herein, we have developed Pt(IV) prodrug conjugated with vorinostat as a multi-functional cancer therapeutic. In this design, the octahedral Pt(IV) prodrug of a DNA damaging anticancer drug cisplatin is tethered to the cancer cell targeting biotin ligand through one of the axial sites and the other axial site of Pt(IV) center is attached to anticancer drug vorinostat (also known as SAHA), a histone deacetylase inhibitor (HDACi) approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma. The designed biotinylated Pt(IV)-SAHA (Biotin-Pt(IV)-SAHA) conjugate is hydrolytically stable but reduced to Pt(II) species under intracellularly relevant conditions and concomitantly releases cisplatin and two of its axial ligands such as SAHA and biotin. The anticancer activity of the conjugate is investigated against a panel of cisplatin-sensitive human cancer cells, including cisplatin-resistant cells. Interestingly, the conjugate exhibited significantly higher cytotoxicity than clinically approved anticancer drug cisplatin and slightly more cytotoxic than HDACi, SAHA, in all the tested cell lines. By combining the platinum(IV) prodrug of cisplatin with SAHA in the conjugate, synergistic cytotoxicity is achieved. The imaging studies revealed that the conjugate is uptaken by cancer cells and shows dose-dependent cell death. The studies on our designed multi-pronged conjugate can be further optimized to enhance its efficacy, paving the way for developing a new class of clinically relevant chemotherapeutic agents.