El Ensayo

Advanced Drug Delivery Reviews
journal homepage: www.elsevier.com/locate/addr

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

School of Pharmacy, CHIRI, WABRI, Curtin University, GPO Box U1987, Perth, Western Australia 6845, Australia Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore 138669, Singapore

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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 inmolecular 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 drugtransport, 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.Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.

Article history: Received 6 August 2011 Accepted 21 November 2011 Available online 28 November 2011 Keywords: Blood–brain barrier Drug delivery Receptor-mediated transport Cell-mediated transport Nanoparticles Liposomes Pathological conditions

Contents 1. 2. 3. 4. Introduction . . . . . . . . . . . . . . . . . . . . . . . .Physiology and biology of the blood–brain barrier . . . . . . Transport routes across the blood–brain barrier . . . . . . . Biological and pathological properties of BBB for drug transport 4.1. Physical barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641 641 642 643 643

Abbreviations: a2M, alpha-2 macroglobulin; Aβ, 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 conjugatednanoparticles; 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...