title: Design, synthesis and biological evaluation of brain targeting l-ascorbic acid prodrugs of ibuprofen with "lock-in" function.
abstract: A novel brain targeting l-ascorbic acid derivatives with "lock-in" function were designed and synthesized as prodrugs to achieve the effective delivery of ibuprofen to brain by glucose transporter 1 (GLUT1) and the Na(+)-dependent vitamin C transporter SVCT2. Ibuprofen-loaded four prodrugs were tested in the animals. Results from the in vivo distribution study after i.v. administration of these four prodrugs and naked ibuprofen indicated that four prodrugs exhibited excellent transport ability across the BBB and significantly increased the level of ibuprofen in brain. Among them, prodrugs 4 showed higher brain concentration. Both biodistribution data and pharmacokinetic parameters suggested that l-ascorbic acid thiamine disulfide delivery system was a promising carrier to enhance CNS drug's delivery ability into brain.
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Boyi
authors.initials: B
authors.lastname: Qu
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xiaocen
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Hai
authors.affiliation: Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: wyong@scu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015195:Drug Design; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D060347:Sodium-Coupled Vitamin C Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D051272:Glucose Transporter Type 1; D011355:Prodrugs; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D001205:Ascorbic Acid; D007052:Ibuprofen
keywords: Brain targeting; Ibuprofen; Prodrugs; Synthesis; Thiamine disulfide; l-Ascorbic acid