A brain-targeting dl-3-n-butylphthalide prodrug to treat ischemic stroke

Stroke is an acute cerebrovascular disease worldwide, featured by stubbornly high mortality and morbidity. 3-n-butylphthalide (NBP) is a first-line agent to treat ischemic stroke, but its unsatisfactorily intracephalic bioavailability is detrimental to the therapeutic efficacy. We have previously developed a series of prodrugs analogous to NBP, however, their conversion rate in the targeted sites cannot meet the clinical demand. Hence, it is imperative to ameliorate the bioavailability and cellular uptake efficiency of the prodrugs, which may be driven by potential energy consuming cationic transporters. Accordingly, we fabricated a novel prodrug named DB-10, which were used tertiary amine to possess active targeting capacity and connected through amide bonds. Moreover, it is noteworthy that DB-10 could rapidly convert into active original drug in the brain to treat acute injury caused by ischemia-reperfusion (I/R). The cytotoxicity of DB-10 was equivalent to that of NBP and would not cause obviously undesired damage in vivo. These encouraging results demonstrate that DB-10 could easily increase the accumulation in the brain site, and significantly improve the treatment effect for ischemic stroke, indicating this biosafety prodrug holds tremendous potential for clinical application prospects.