Blood-brain barrier transport machineries and targeted therapy of brain diseases

Abstract

Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB), drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS). However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs). Conclusions: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs) can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain.

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

“…In the past few years various nanoparticle (NP) types have been investigated to develop nanosystems meeting the needs of effective therapies for neurological diseases,12 also leading to a broader understanding of the mechanism of NP uptake in the brain 13. Among the many achievements, dendrimers showed high potential for a noninvasive therapy.…”

Changes in Gene Expression Profiles in Adult Rat Brain Structures after Neonatal Action of Dipeptidyl Peptidase-IV Inhibitors

“…Given that tripeptides usually cross the blood-brain barrier BBB through peptide transporters [42], we can assume that tripeptide diprotin A could penetrate the BBB, thus affecting gene expression in different brain structures. The penetration of gliptins through the BBB is difficult [43].…”

The Significance of Nanomedicine in Brain-Targeted Drug Delivery: Crossing Blood-Brain Barriers

“…Nevertheless, large molecules such as cytokines and neurotrophins enter the brain via receptormediated endocytosis, whereas specific transporters mediate the entrance of essential nutrients, including amino acids, glucose and ketone bodies [10]. In general, under normal physiological conditions, few substances are capable to surpass the BBB by carrier-mediated transport, receptor-mediated endocytosis, and scantly through passive diffusion and adsorptive transcytosis.…”

“…In general, under normal physiological conditions, few substances are capable to surpass the BBB by carrier-mediated transport, receptor-mediated endocytosis, and scantly through passive diffusion and adsorptive transcytosis. However, the possibility for molecule to diffuse passively across BBB is very limited, and confined to lipid soluble molecules with a molecular weight of < 400 Da [10].…”