ABSTRACT
The central nervous system (CNS) is well-protected from the fluctuating milieu of the blood by a pair of highly functional barricades; the aforementioned blood-brain barrier (BBB), and the blood-cerebrospinal fluid barrier. Peptide prodrug delivery into the CNS remains an important and intriguing field as many peptides have unfulfilled neurotherapeutic potentials for a wide variety of maladies affecting the CNS and currently without efficacious pharmacological interventions. The great advantage of prodrug design is that ionizable functional groups can be transiently masked for BBB transport by strategically selected bioreversible chemical modifications to make the prodrugs neutral at physiological conditions, and also to balance water solubility with membrane affinity. The prodrug, however, performed marginally; one possible reason could be insufficient brain targeting with the inherently unstable dihydropyridine. The lipoamino acid was included into the prodrug construct to augment not only lipophilicity but also to introduce amphiphilicity to facilitate the prodrug’s interaction with cell membranes.
