Developing a Palladium(II) Agent to Overcome Multidrug Resistance and Metastasis of Liver Tumor by Targeted Multiacting on Tumor Cell, Inactivating Cancer-Associated Fibroblast and Activating Immune Response

To targeted overcome the multidrug resistance (MDR) and metastasis of liver tumors, we proposed to develop a palladium (Pd) agent based on a specific residue of human serum albumin (HSA) for multiacting on tumor cell and other components in the tumor microenvironment. To this end, a series of Pd(II) 2-acetylpyridine thiosemicarbazone compounds were optimized to obtain a Pd(II) compound (5b) with significant cytotoxicity against HepG2/ADM cells. Subsequently, we constructed a HSA-5b complex delivery system and revealed the structural mechanism of HSA delivering 5b. Importantly, 5b/HSA-5b effectively inhibited the growth and metastasis of multidrug resistant liver tumors, and HSA enhanced the targeting ability of 5b and reduced its side effects <i>in vivo</i>. Furthermore, we confirmed the mechanisms of 5b/HSA-5b integrating to overcome MDR and metastasis of liver tumors: multiacting on cancer cell, activating immune response, and inactivating cancer-associated fibroblasts.