Bioconjugation is one of the most promising strategies to improve drug delivery, especially in cancer therapy. Biomolecules such as bile acids (BAs) have been intensively explored as carriers, due to their peculiar physicochemical properties and biocompatibility. BAs trafficking is regulated by intracellular lipid-binding proteins and their transport in the liver can be studied using chicken liver Bile Acid-Binding Proteins (cL-BABPs) as a reference model. Therefore, we conceived the idea of developing a BA-conjugate with Mirin, an exonuclease inhibitor of Mre11 endowed with different anticancer activities, to direct its transport to the liver. Following computational analysis of various BAs in complex with cL-BABP, we identified cholic acid (CA) as the most promising candidate as carrier, leading to the synthesis of a novel bioconjugate named CA-M11. As predicted by computational data and confirmed by X-ray crystallographic studies, CA-M11 was able to accommodate into the binding pocket of BABP. Hence, it can enter BAs trafficking in the hepatic compartment and here release Mirin. The effect of CA-M11, evaluated in combination with varying concentrations of Doxorubicin on HepG2 cell line, demonstrated a significant increase in cell mortality compared to the use of the cytotoxic drug or Mirin alone, thus highlighting chemo-sensitizing properties. The promising results regarding plasma stability for CA-M11 validate its potential as a valuable agent or adjuvant for hepatic cancer therapy.

生物共轭是改善药物递送最有前途的策略之一，特别是在癌症治疗中。胆汁酸（BA）等生物分子由于其独特的理化性质和生物相容性，作为载体已被广泛探索。 BA 的运输受到细胞内脂质结合蛋白的调节，并且可以使用鸡肝胆汁酸结合蛋白 (cL-BABP) 作为参考模型来研究它们在肝脏中的运输。因此，我们想到开发 BA 与 Mirin（一种具有不同抗癌活性的 Mre11 核酸外切酶抑制剂）的结合物，以引导其转运至肝脏。对与 cL-BABP 复合的各种 BA 进行计算分析后，我们确定胆酸 (CA) 是最有希望的载体候选者，从而合成了一种名为 CA-M11 的新型生物缀合物。正如计算数据预测和 X 射线晶体学研究证实的那样，CA-M11 能够容纳到 BABP 的结合口袋中。因此，它可以进入肝室中的 BA 运输并在此释放味醂。结合不同浓度的多柔比星对 HepG2 细胞系的作用进行评估，发现与单独使用细胞毒性药物或味霖相比，CA-M11 的细胞死亡率显着增加，从而突出了化学敏化特性。 CA-M11 血浆稳定性的有希望的结果验证了其作为肝癌治疗的有价值的药物或佐剂的潜力。