Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Abstract

Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review.

Keywords: AD, Alzheimer's disease; AMT, alpha-methyl-l-tryptophan; Aβ, amyloid beta; BACE1, β-secretase 1; BBB, blood–brain barrier; BDNF, brain derived neurotrophic factor; BTB, blood–brain tumor barrier; Blood–brain barrier; Brain diseases; Brain-targeting; CMT, carrier-mediated transportation; DTPA-Gd, Gd-diethyltriaminepentaacetic acid; Drug delivery systems; EPR, enhanced permeability and retention; GLUT1, glucose transporter-1; Gd, gadolinium; ICAM-1, intercellular adhesion molecule-1; KATP, ATP-sensitive potassium channels; KCa, calcium-dependent potassium channels; LAT1, L-type amino acid transporter 1; LDL, low density lipoprotein; LDLR, LDL receptor; LFA-1, lymphocyte function associated antigen-1; LRP1, LDLR-related protein 1; MFSD2A, major facilitator superfamily domain-containing protein 2a; MMP9, metalloproteinase-9; MRI, magnetic resonance imaging; NPs, nanoparticles; Nanoparticles; P-gp, P-glycoprotein; PD, Parkinson's disease; PEG, polyethyleneglycol; PEG-PLGA, polyethyleneglycol-poly(lactic-co-glycolic acid); PLGA, poly(lactic-co-glycolic acid); PSMA, prostate-specific membrane antigen; RAGE, receptor for advanced glycosylation end products; RBC, red blood cell; RMT, receptor-mediated transcytosis; ROS, reactive oxygen species; TBI, traumatic brain injury; TJ, tight junction; TfR, transferrin receptor; VEGF, vascular endothelial growth factor; ZO1, zona occludens 1; siRNA, short interfering RNA; tPA, tissue plasminogen activator.