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Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation

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Abstract

Drug delivery to the brain is hindered by the presence of the blood–brain barrier (BBB). Although the BBB restricts the passage of many substances, it is actually selectively permeable to nutrients necessary for healthy brain function. To accomplish the task of nutrient transport, the brain endothelium is endowed with a diverse collection of molecular transport systems. One such class of transport system, known as a receptor-mediated transcytosis (RMT), employs the vesicular trafficking machinery of the endothelium to transport substrates between blood and brain. If appropriately targeted, RMT systems can also be used to shuttle a wide range of therapeutics into the brain in a noninvasive manner. Over the last decade, there have been significant developments in the arena of RMT-based brain drug transport, and this review will focus on those approaches that have been validated in an in vivo setting.

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Abbreviations

ADR:

adriamycin

AEM:

analytical electron microscopy

AUC:

area under the curve

Av:

avidin

AZT:

azidothymidine

BBB:

blood–brain barrier

BDNF:

brain-derived neurotrophic factor

bFGF:

basic fibroblast growth factor

DSPE:

distearoylphosphatidylethanolamine

EGFR:

human epidermal growth factor receptor

FGF-2:

fibroblast growth factor-2

GFAP:

glial fibrillary acidic protein

GUS:

β-glucuronidase

HB-EGF:

heparin binding epidermal growth factor-like growth factor

HCEC:

human cerebromicrovascular endothelial cells

HD:

Huntington’s disease

HIR:

human insulin receptor

HRP:

horseradish peroxidase

IGF-II:

insulin-like growth factor II

LDL:

low density lipoprotein

LRP1/2:

low density lipoprotein receptor-related protein 1/2

M6P:

mannose 6-phosphate

MAb:

monoclonal antibody

MCAO:

middle cerebral artery occlusion

NGF:

nerve growth factor

NHS:

N-hydroxysuccinimide

ODN:

oligonucleotides

PBCA:

poly(butyl cyanoacrylate)

PEG:

poly(ethylene glycol)

P-GUS:

phosphorylated β-glucuronidase

PNA:

peptide nucleic acid

RAP:

receptor-associated protein

RES:

reticuloendothelial system

RMT:

receptor-mediated transcytosis

rsCD4:

recombinant human soluble CD4

SA/B:

streptavidin/ biotin

SATA:

N-succinimidyl S-acetylthioacetate

scFv:

single-chain variable fragment

sdAb:

single-domain antibodies

SMCC:

Succinimidyl 4-[N-maleimidomethyl]-cyclohexane-1-carboxylate

SV40:

simian virus 40

Tf:

transferrin

TfR:

transferrin receptor

TH:

tyrosine hydroxylase

tPA:

tissue-type plasminogen activator

VIP:

vasoactive intestinal peptide

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Acknowledgments

This work was in part funded by National Institutes of Health Grant NS052649. A.R.J. is the recipient of a National Science Foundation Graduate Research Fellowship.

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  1. Department of Chemical and Biological Engineering, University of Wisconsin-Madison, 1415 Engineering Drive, Madison, Wisconsin, 53706, USA

    Angela R. Jones & Eric V. Shusta

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  1. Angela R. Jones
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Correspondence to Eric V. Shusta.

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Jones, A.R., Shusta, E.V. Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation. Pharm Res 24, 1759–1771 (2007). https://doi.org/10.1007/s11095-007-9379-0

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