State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources/Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, Guangxi 541004, PR China.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, PR China.
J Med Chem. 2024 Sep 26;67(18):16296-16310. doi: 10.1021/acs.jmedchem.4c01175. Epub 2024 Sep 5.
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 . 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.
为了有针对性地克服肝癌的多药耐药性（MDR）和转移，我们提出开发一种基于人血清白蛋白（HSA）特定残基的钯（Pd）试剂，以对肿瘤细胞和肿瘤微环境中的其他成分进行多作用。为此，我们对一系列 Pd(II) 2-乙酰吡啶缩氨基硫脲化合物进行了优化，以获得对 HepG2/ADM 细胞具有显著细胞毒性的 Pd(II)化合物（5b）。随后，我们构建了 HSA-5b 复合物递送系统，并揭示了 HSA 递送 5b 的结构机制。重要的是，5b/HSA-5b 有效抑制了多药耐药性肝癌的生长和转移，HSA 增强了 5b 的靶向能力并降低了其副作用。此外，我们证实了 5b/HSA-5b 整合以克服肝癌 MDR 和转移的机制：对癌细胞的多作用、激活免疫反应和失活癌相关成纤维细胞。
