Developing\na Palladium(II) Agent to Overcome Multidrug\nResistance and Metastasis of Liver Tumor by Targeted Multiacting on\nTumor Cell, Inactivating Cancer-Associated Fibroblast and Activating\nImmune Response

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