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 in vivo. 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.