A rapid albumin-binding 5-fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity.
A rapid albumin-binding 5-fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity.
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DOI：
10.1039/c6bm00884d
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发表时间：
2017-02
影响因子：
6.6
通讯作者：
Dongyang Zhao;Huicong Zhang;Wenhui Tao;Wei Wei-Wei;Jin Sun;Zhonggui He
中科院分区：
文献类型：
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作者：
Dongyang Zhao;Huicong Zhang;Wenhui Tao;Wei Wei-Wei;Jin Sun;Zhonggui He
5-氟尿嘧啶(5-FU)是一种广泛用于治疗多种实体肿瘤的抗代谢药物。然而，由于其在血液循环中的滞留时间很短，且在体内的非特异性分布，极大地阻碍了其临床应用。为了克服这些挑战，我们设计了1-烷基甲酰氧甲基5-氟尿嘧啶，并将其与马来酰亚胺基团连接，形成了白蛋白结合型5-氟尿嘧啶前药，命名为EMC-5-FU。与牛血清白蛋白(BSA)和新鲜大鼠血的体外孵育证明，前药能迅速与半胱氨酸-34结合形成药物-白蛋白偶联纳米药物。结合物BSA-EMC-5-FU在酸性和中性条件下稳定，但在碱性溶液中释放5-FU不稳定，并用于血浆中总5-FU浓度的测定。给SD大鼠静脉注射EMC-5-FU后，总的5-FU的T1/2和AUC值显著增加，分别是静脉注射5-FU的43倍和93倍。体内荧光图像间接证实了EMC-5-FU在肿瘤中的选择性蓄积。在H22荷瘤小鼠模型中，EMC-5-FU的抑瘤作用比静脉注射5-FU更有效。总之，快速白蛋白结合前药策略解决了与抗癌药物循环半衰期差和非特异性分布有关的问题，并为体内形成纳米药物在临床癌症治疗中的发展铺平了道路。
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 t1/2 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.