一种胆酸偶联的奥沙利铂前药LLC-202被开发为肝癌的新型前药。将3-NH2-环丁烷-1,1-二甲酸酯用作氧化奥沙利铂类似物和胆酸部分之间的连接剂，通过酰胺键将胆酸牢固地连接到连接剂上。药代动力学实验表明，LLC-202经静脉注射Sprague-Dawley大鼠后主要分布和富集于肝脏，呈现出肝定向特性。与奥沙利铂相比，LLC-202更容易被人类肝癌细胞吸收而不伤害正常人类肝细胞。LLC-202在治疗C57BL/6小鼠原发性肝细胞癌方面表现出更高的体外抗癌活性和与奥沙利铂相当的疗效，可以通过诱导凋亡和抑制癌细胞增殖显著延长肿瘤携带小鼠的生存时间。此外，LLC-202对正常人类肝细胞的细胞毒性比奥沙利铂低。其静脉注射后对健康昆明（KM）小鼠的急性毒性与奥沙利铂相当。组织病理学检查表明，LLC-202在小鼠中的主要毒性是骨髓造血细胞的抑制。结果表明，LLC-202作为一种特异性肝癌新型前药的进一步开发有着巨大的潜力。版权所有©2023 Elsevier公司。保留所有权利。

A cholic acid-conjugated oxaliplatin, LLC-202, is developed as a novel prodrug for liver cancer. The conjugate is obtained by using 3-NH2-cyclobutane-1,1-dicarboxylate as a linker between the oxaliplatin analogue and cholic acid moiety and cholic acid is strongly bonded to the linker via an amide bond. Pharmacokinetic experiment shows that LLC-202 is mainly distributed and accumulated in the liver after intravenous administration to Sprague-Dawley rats, revealing the liver-targeting profile. Compared to oxaliplatin, LLC-202 is more easily taken up by human liver cancer cells than normal human liver cells. LLC-202 exhibits higher in vitro anticancer activity and higher efficacy comparable to oxaliplatin in treating primary hepatocellular carcinoma in C57BL/6 mice. It can significantly prolong the survival time of tumor-bearing mice by inducing apoptosis and inhibiting proliferation of cancer cells. In addition, LLC-202 shows less cytotoxicity toward normal human liver cells than oxaliplatin. Its acute toxicity in healthy Kunming (KM) mice after i.v. administration is comparable to oxaliplatin. Histopathological examination reveals that the main toxicity of LLC-202 in mice is the depression of bone marrow hematopoietic cells. The results suggest that LLC-202 has great potential for further development as a new prodrug specific for liver cancer.Copyright © 2023 Elsevier Inc. All rights reserved.