Dai Xiaoshuang, Mei Ke, Liu Jianpeng, Sun Bin, Qiu Neng
College of Ecology and Environment, Chengdu University of Technology, Chengdu 610059, China.
College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu 610059, China.
Bioorg Med Chem Lett. 2025 Jul 1;122:130209. doi: 10.1016/j.bmcl.2025.130209. Epub 2025 Mar 25.
In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.
在本研究中，阿魏酸（FA）通过二硫键与生物素缀合，以提高其抗癌活性。所得缀合物（FA-SS-Bio）通过质子核磁共振（H NMR）进行表征，与FA的晶体性质不同，呈现无定形结构。FA-SS-Bio在还原和氧化条件下表现出加速的药物释放。细胞摄取研究和分子对接证实，生物素化显著增加了生物素受体（BR）阳性的HeLa和MCF-7细胞对药物的摄取，揭示了生物素与BR之间的强相互作用。此外，FA-SS-Bio的细胞毒性显著提高，其IC值分别比游离FA对HeLa和MCF-7细胞的IC值低2.94倍和2.95倍。用生物素阻断BR以浓度依赖的方式降低了FA-SS-Bio的细胞毒性，证实了生物素介导的靶向作用。凋亡分析表明，由于生物素和二硫键，FA诱导的凋亡增强。FA-SS-Bio表现出优异的血液相容性，溶血率低于0.5%，而FA的溶血率约为1.5%。此外，FA-SS-Bio在MCF-10 A细胞中的细胞活力高于癌细胞，突出了其良好的安全性。这些发现为设计用于改善癌症治疗的前药缀合物提供了新的视角。
