Synthesis and biological evaluation of cholic acid-conjugated oxaliplatin as a new prodrug for liver cancer.

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.