title: A rapid albumin-binding 5-fluorouracil prodrug with a prolonged circulation time and enhanced antitumor activity.
abstract: 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 t1/2and 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Huicong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Jin
authors.identifier: http://orcid.org/0000-0002-5907-3875
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China. sunjin66@21cn.com hezhonggui@vip.163.com.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D002417:Cattle; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D006207:Half-Life; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D012710:Serum Albumin, Bovine; D005472:Fluorouracil