Modern methods for delivery of drugs across the blood–brain barrier

https://doi.org/10.1016/j.addr.2011.11.010Get rights and content

Abstract

The blood–brain barrier (BBB) is a highly regulated and efficient barrier that provides a sanctuary to the brain. It is designed to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. Unfortunately, drug transport to the brain is hampered by this almost impermeable, highly selective and well coordinated barrier. With progress in molecular biology, the BBB is better understood, particularly under different pathological conditions. This review will discuss the barrier issue from a biological and pathological perspective to provide a better insight to the challenges and opportunities associated with the BBB. Modern methods which can take advantage of these opportunities will be reviewed. Applications of nanotechnology in drug transport, receptor-mediated targeting and transport, and finally cell-mediated drug transport will also be covered in the review. The challenge of delivering an effective therapy to the brain is formidable; solutions will likely involve concerted multidisciplinary approaches that take into account BBB biology as well as the unique features associated with the pathological condition to be treated.

Abbreviations

a2M
alpha-2 macroglobulin
amyloid β
ABC
ATP binding cassette
AD
Alzheimer's disease
AIDS
autoimmunodeficiency syndrome
AJ
adherens junction
AMT
adsorptive-mediated transport
AMP
adenosine monophosphate
ANG1005
angiopep 2 conjugated with 3 molecules of paclitaxel
Antp
Antennapedia
APP
amyloid beta precursor protein
ApoE
Apolipoprotein E
ATP
adenosine triphosphate
AUC
area under curve
BBB
blood–brain barrier
BCSFB
blood–cerebrospinal fluid barrier
BSA-NP
bovine serum albumin conjugated nanoparticles
cAMP
cyclic AMP
CBSA
cationic bovine serum albumin
CBSA-NP
CBSA conjugated PEG-PLA nanoparticles
CED
convection enhanced diffusion
CHP
hydrophobic cholesterol groups
CMC
critical micelle concentration
CMT
carrier-mediated transport
CNS
central nervous system
CPP
cell penetrating peptide
CRM
cross reacting material
CSF
cerebrospinal fluid
DT
diphtheria toxin
DTR
diphtheria toxin receptor
EAE
experimental autoimmune encephalomyelitis
EO
ethylene oxide
EC
endothelial cell
EMF
electromagnetic fields
FBP
fusion sequence-based peptide
g7
similopioid peptide
GMP
guanosine monophosphate
HB-EGF
heparin binding epidermal growth factor
HIRMAb
human insulin receptor monoclonal antibody
HIV
human immunodeficiency virus
HLB
hydrophobic–hydrophilic balance
HSA
human serum albumin
HSP-96
heat shock protein 96
HUVEC
human umbilical vein endothelial cells
ICH
intercerebral haemorrhage
ICV
intracerebroventricular
IgG
immunoglobulin G
IL
interleukin
INF
interferon
JAM
junction adhesion molecules
LDL
low density lipoprotein
LDLR
low density lipoprotein receptor
Lf
lactoferrin
LMV
large multilamellar vesicles
LPA
lysophosphatidic acid
LRP
lipoprotein receptor protein
LUV
large unilamellar vesicles
MAP
model amphipathic peptide
MAPK
mitogen activated protein kinase
MCP
monocyte chemotactic protein
MHC
major histocompatibility complex
MLCK
myosin light chain kinase
MP
mononuclear phagocytes
MRP
multidrug resistant protein
MS
multiple sclerosis
NOS
nitric oxide syntheses
NP
nanoparticles
NVU
neurovascular unit
P97
melanotransferrin
PAI-1
plasminogen activator inhibitor 1
PHDCA
poly(hexadecylcyanoacrylate)
PBCA
poly(butylcyanoacrylate)
PEG
polyethylene glycol
PEG-PCL
PEG-polycaprolactone
PEG-G-CSF
PEGylated-recombinant methionyl human granulocyted colony stimulating factor
PEG-PLA
polyethylene glycol-polylactic acid
P-gp
P-glycoprotein
PKA
protein kinase A
PKC
protein kinase C
PKG
protein kinase G
PLGA
poly(d,l-lactide-co-glycolide)
PO
propylene oxide
PTD
protein transduction domain
PTK
protein tyrosine kinase
Qdots
quantum dots
RAP
receptor associated protein
RES
reticuloendothelial system
REV
reverse phase evaporation vesicles
RMT
receptor-mediated transport
R123
rhodamine 123
SA
sialic acid residue
SBP
sequence signal-based peptide
SUV
small unilamellar vesicles
TAT
HIV-1 trans-activating transcriptor
TEM
transmission electron microscopy
TER
transendothelial electrical resistance
TfR
transferrin receptor
TJ
tight junction
TNF
tumour necrosis factors
tPA
tissue plasminogen activator
VE
vascular endothelial
VEGF
vascular endothelial growth factor
ZO
zonula occludens

Keywords

Blood–brain barrier
Drug delivery
Receptor-mediated transport
Cell-mediated transport
Nanoparticles
Liposomes
Pathological conditions

Cited by (0)

This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery of Therapeutics to the Central Nervous System”.

1

L Liu is currently funded as an Australian Postdoctoral Fellow by ARC Discovery Project DP110104599 at Chemical Engineering, Curtin University.

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