Design, synthesis and biological evaluation of brain targeting l-ascorbic acid prodrugs of ibuprofen with “lock-in” function

•The new brain targeting l-ascorbic acid-prodrugs with “lock-in” function were designed and synthesized.•Ibuprofen-loaded four prodrugs were tested in the animals.•The results indicated that TDS system plays an important role to improve the bioavailability.•We reported a novel l-ascorbic acid thiamine disulfide delivery system.

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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide