Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

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.

Lipidization as a tool toward peptide therapeutics

“…The process of lipidization falls in the groups of post-translational modifications called acylation. Lipidization is an approach that may allow modified peptides to cross the blood-brain barrier (BBB) (Jain et al., 2013 ; Erak et al., 2018 ; Menacho-Melgar et al., 2019 ; Botti et al., 2021 ; Hanna et al., 2022 ). This modification is also FDA-approved (Menacho-Melgar et al., 2019 ), so it is highly desirable to invent peptide drugs using this modification to achieve the best pharmacokinetic and pharmacodynamic properties.…”

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases

“…The use of prodrugs is another widely used strategy based on increasing the lipophilic nature of neuroactive agents using receptor-and carrier-mediated BBB transport. 142,143 Hydrophilic drugs are chemically transformed into lipophilic prodrugs by masking polar functional groups with nonpolar and lipophilic substituents. The prodrugs obtained through such a ''lipidization'' process are inactive agents in vivo, but can easily access the brain where their conversion to parent active agents is induced by enzymatic or chemical processes.…”

A Review of Non-Invasive Drug Delivery through Respiratory Routes

“…However, the precise drug delivery mechanism of the nasal cavity to the CNS is not fully understood. Several reports demonstrate that nose-to-brain drug delivery is mainly mediated by olfactory and trigeminal nerve pathways located at the roof of the nasal cavity [34]. The functional pathway through which drugs pass into the CNS from structures deep in the nose innervated by the cranial nerve is called "nose-to-brain" transport [35].…”