Design, Synthesis and Evaluation of Dual-targeting Prodrug Co-modified by Organic Amine and L-ascorbic Acid for CNS Delivery

Background: L-ascorbic acid and organic amine showed a good brain targeting ability. However, there was no report on the combination of L-ascorbic acid and organic amine as a carrier for central nervous system (CNS) drug delivery. Objective: To synthesize the ibuprofen prodrug co-modified by organic amine and L-ascorbic acid, and evaluate its brain targeting ability. Methods: A dual-targeting ibuprofen prodrug 2 co-modified by organic amine and L-ascorbic acid was designed and synthesized. HEK293T cells were used to evaluate the cytotoxicity. The chemical and metabolic stability was investigated in buffer solutions, plasma and brain homogenate, respectively. Furthermore, the brain targeting ability of the prodrug was evaluated in vivo compared with prodrug 1 and naked ibuprofen. Results: The novel prodrug 2 exhibited excellent ability to penetrate the brain-blood barrier (BBB) and significantly increased the level of ibuprofen in brain. The relative uptake efficiency and concentration efficiency were enhanced by 3.16 and 4.92 times than that of naked ibuprofen, respectively. Conclusion: The results of this study indicated that organic amine and L-ascorbic acid was a splendid carrier to enhance the delivery of CNS drugs into brain. These results provided an effective entry to the development of new brain targeting drugs.