Hopping the Hurdle: Strategies to Enhance the Molecular Delivery to the Brain through the Blood-Brain Barrier

Abstract

Modern medicine has allowed for many advances in neurological and neurodegenerative disease (ND). However, the number of patients suffering from brain diseases is ever increasing and the treatment of brain diseases remains an issue, as drug efficacy is dramatically reduced due to the existence of the unique vascular structure, namely the blood-brain barrier (BBB). Several approaches to enhance drug delivery to the brain have been investigated but many have proven to be unsuccessful due to limited transport or damage induced in the BBB. Alternative approaches to enhance molecular delivery to the brain have been revealed in recent studies through the existence of molecular delivery pathways that regulate the passage of peripheral molecules. In this review, we present recent advancements of the basic research for these delivery pathways as well as examples of promising ventures to overcome the molecular hurdles that will enhance therapeutic interventions in the brain and potentially save the lives of millions of patients.

Keywords: blood–brain barrier; drug delivery; neurodegenerative disease.

Figure 1

Schematic representation of the basic structure of the BBB, cross-sectionally and cell structure including astrocytes, pericytes, endothelial cells, TJs and associated neurons. TJs—tight junctions.

Figure 2

Schematic representation for various modalities of transport across the BBB. RMT—receptor-mediated transport; AMT—adsorption-mediated transport; CMT—carrier-mediated transport; JAM—junctional adhesion molecules; Pgp—P-glycoprotein; BCRP—breast cancer resistance protein; MARP1–5—muscle ankyrin-repeat proteins 1–5. Adapted from Pulgar et al. [23].

Figure 3

Basic structure of ABC transporters, whereby through ATP hydrolysis, causes a conformational change that drives the substrate across the membrane. TMD—transmembrane domain; NBD—nucleotide-binding domain; ATP—adenosine triphosphate; ADP—adenosine diphosphate; SBP—substrate-binding protein. Adapted from CUSABIO (https://www.cusabio.com/Transmembrane/A-transport-machine-ATP-binding-cassette.html (accessed on 30 December 2023)).

Figure 4

Schematic representation for approaches to increase BBB permeability, including the activation of AR and NMDA receptors, the increasing of junctional gaps and drug treatment such as Regadenoson. GPCR—G-protein-coupled receptor; TJs—tight junctions; NMDA—N-methyl-D-aspartate; PKC—protein kinase C; MLCK—myosin light chain kinase; Pgp—P-glycoprotein; AR—adenosine receptor; MDR—multi-drug resistance protein.

Figure 5

Schematic representation of carrier systems to increase drug delivery across the BBB. Methods described include metal nanoparticles, quantum dots, lipid composites, protein nanparticles and antibody-drug conjugates.

Figure 6

Schematic illustration of the impediment of drug delivery to the brain, due to ABC transporter activity. EC—endothelial cell; ATP—adenosine triphosphate; ADP—adenosine diphosphate; P-gp—P-glycoprotein; BCRP—breast cancer resistance protein; MRPs—multi-drug resistance protein. Adapted from Gil-Martins et al. [177].