Zhao Siyuan, Wang Tiansi, Shi Kourong, Li Ting, Zhu Qiuzhen, Li Yuan, Xin Beiwei, Wu Xin, Fan Wei
Department of Pharmacy, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No 358, Datong Road, Gaoqiao, Pudong New Area, 200137, Shanghai, China.
Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, China.
Invest New Drugs. 2025 Feb;43(1):30-41. doi: 10.1007/s10637-024-01488-2. Epub 2024 Dec 21.
To extend the short half-life of fluorouracil (Fu), enhance its tumor targeting, improve efficacy, and reduce side effects, providing a new approach for colorectal cancer treatment. Fluorouracil was hydroxylated and conjugated with methotrexate to form a 5-fluorouracil-methotrexate conjugate (MF). This was complexed with sulfobutyl ether-β-cyclodextrin (MF-SEBCD) using a stirring method to create an injectable formulation. In vitro studies assessed the conversion of MF-SEBCD in plasma and its antitumor activity. In vivo studies examined antitumor activity, preliminary safety, pharmacokinetics, and tissue distribution. MF was synthesized with a 25% yield and purity above 95%. The water solubility of MF increased by 92-fold with MF-SEBCD preparation. In vitro, MF-SEBCD effectively converted into Fu in plasma and showed strong antitumor activity, with IC50 values of 0.51, 1.29, and 1.26 µM for MC38, HT29, and 4T1 cells, respectively. In vivo, MF-SEBCD achieved a tumor inhibition rate of 57.08%. Pharmacokinetic studies showed that MF-SEBCD extended Fu's half-life to 47 min, nearly double that of Fu injection. Tissue distribution analysis confirmed improved tumor targeting. MF-SEBCD effectively prolongs Fu's half-life, enhances tumor targeting, increases antitumor efficacy, and reduces side effects, offering a promising approach for colorectal cancer treatment.
为延长氟尿嘧啶（Fu）的短半衰期，增强其肿瘤靶向性，提高疗效并减少副作用，为结直肠癌治疗提供一种新方法。将氟尿嘧啶进行羟基化并与甲氨蝶呤共轭形成5-氟尿嘧啶-甲氨蝶呤共轭物（MF）。采用搅拌法将其与磺丁基醚-β-环糊精络合（MF-SEBCD）以制备可注射制剂。体外研究评估了MF-SEBCD在血浆中的转化及其抗肿瘤活性。体内研究考察了抗肿瘤活性、初步安全性、药代动力学和组织分布。MF的合成产率为25%，纯度高于95%。制备MF-SEBCD后，MF的水溶性增加了92倍。在体外，MF-SEBCD在血浆中有效转化为Fu，并表现出较强的抗肿瘤活性，对MC38、HT29和4T1细胞的IC50值分别为0.51、1.29和1.26μM。在体内，MF-SEBCD的肿瘤抑制率达到57.08%。药代动力学研究表明，MF-SEBCD将Fu的半衰期延长至47分钟，几乎是Fu注射剂的两倍。组织分布分析证实肿瘤靶向性得到改善。MF-SEBCD有效延长了Fu的半衰期，增强了肿瘤靶向性，提高了抗肿瘤疗效并减少了副作用，为结直肠癌治疗提供了一种有前景的方法。
