Abstract
About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.
Highlights
blood brain barrier (BBB) segregates the brain interstitial fluid (ISF) from the bloodstream and is constituted by a monolayer of specialized endothelial cells of brain microvessels lined by the basal lamina and strictly connected by tight junctions (TJs) that hamper the presence of fenestrae
As a consequence, during the past twenty years, the prodrug approach was proposed to overcome this drawback according to two main strategies: (i) the drug modification into a “pseudonutrients” structure, able to be transported by Carrier Mediated Transport (CMT); (ii) the conjugation of neuroactive drugs with nutrients known to be transported by CMT
About 40 years ago lipidization appeared as one of the first prodrug approaches for brain targeting of neuroactive agents
Summary
The drugs currently used against brain diseases constitute about 5% of the drug market and are limited essentially to treating chronic pain, schizophrenia, epilepsy, and depression. The endothelial cells of the capillaries within the choroid plexus are characterized by intercellular gaps and fenestrations In this case, the ependymal cells of the choroid plexus are strictly connected by TJs, forming the BCSFB, whose role is the secretion and regulation of the cerebrospinal fluid (CSF) [1]. The ependymal cells of the choroid plexus are strictly connected by TJs, forming the BCSFB, whose role is the secretion and regulation of the cerebrospinal fluid (CSF) [1] Another important physiological barrier is the blood-retinal barrier (BRB), constituted by retinal capillary endothelial (inner BRB) and retinal pigment epithelial (RPE) cells TJs of the outer BRB allow it to strictly regulate the flux of molecules into and out of the retina [1,7] to the BBB or BCSFB of the CNS
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