Zhao Dongyang, Zhang Huicong, Tao Wenhui, Wei Wei, Sun Jin, He Zhonggui
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
Biomater Sci. 2017 Feb 28;5(3):502-510. doi: 10.1039/c6bm00884d.
5-Fluorouracil (5-FU) is an antimetabolite widely used in the treatment of a variety of solid tumors. However, its clinical applications are greatly hindered by a very short residence time in blood circulation and non-specific distribution in the body. In order to overcome these challenges, 1-alkylcarbonyloxymethyl 5-FU was designed and linked with a maleimide group to form an albumin-binding 5-FU prodrug, named EMC-5-FU. In vitro incubation with bovine serum albumin (BSA) and fresh rat blood proved that the prodrug bound rapidly to cysteine-34 to form the drug-albumin conjugate nanomedicine. The conjugate BSA-EMC-5-FU was stable under acidic and neutral conditions but an unstable compound to release 5-FU in alkaline solution, and such a property was used for the determination of total 5-FU concentration in plasma. The t and AUC values of total 5-FU after an intravenous injection of EMC-5-FU to SD rats were significantly increased, about 43-fold and 93-fold higher than those of 5-FU following 5-FU intravenous administration, respectively. In vivo fluorescence images of EMC-Cy5 indirectly demonstrated the selective tumor accumulation of EMC-5-FU. In H22 tumor-bearing mice models, treatment with EMC-5-FU was more efficacious in tumor inhibition compared to 5-FU intravenous administration. In conclusion, a rapid albumin-binding prodrug strategy addresses concerns related to the poor circulation half-life and non-specific distribution of anticancer drugs, and paves the way for the development of in vivo-forming nanomedicines in clinical cancer therapy.
5-氟尿嘧啶（5-FU）是一种广泛用于治疗多种实体瘤的抗代谢药物。然而，其临床应用因在血液循环中的停留时间极短以及在体内的非特异性分布而受到极大阻碍。为了克服这些挑战，设计了1-烷基羰基氧甲基5-FU并将其与马来酰亚胺基团相连，形成一种白蛋白结合型5-FU前药，命名为EMC-5-FU。与牛血清白蛋白（BSA）和新鲜大鼠血液进行体外孵育证明，该前药能迅速与半胱氨酸-34结合，形成药物-白蛋白缀合物纳米药物。缀合物BSA-EMC-5-FU在酸性和中性条件下稳定，但在碱性溶液中不稳定，会释放5-FU，这种性质被用于测定血浆中总5-FU浓度。将EMC-5-FU静脉注射到SD大鼠体内后，总5-FU的t和AUC值显著增加，分别比静脉注射5-FU后5-FU的t和AUC值高约43倍和93倍。EMC-Cy5的体内荧光图像间接证明了EMC-5-FU在肿瘤中的选择性蓄积。在H22荷瘤小鼠模型中，与静脉注射5-FU相比，EMC-5-FU治疗对肿瘤的抑制效果更好。总之，一种快速的白蛋白结合前药策略解决了与抗癌药物循环半衰期短和非特异性分布相关的问题，并为临床癌症治疗中体内形成纳米药物的开发铺平了道路。
