Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

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Abstract

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

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Intranasal delivery of biologics to the central nervous system.

Jeffrey J. Lochhead, Robert Thorne (2012)

Treatment of central nervous system (CNS) diseases is very difficult due to the blood-brain barrier's (BBB) ability to severely restrict entry of all but small, non-polar compounds. Intranasal administration is a non-invasive method of drug delivery which may bypass the BBB to allow therapeutic substances direct access to the CNS. Intranasal delivery of large molecular weight biologics such as proteins, gene vectors, and stem cells is a potentially useful strategy to treat a variety of diseases/disorders of the CNS including stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, epilepsy, and psychiatric disorders. Here we give an overview of relevant nasal anatomy and physiology and discuss the pathways and mechanisms likely involved in drug transport from the nasal epithelium to the CNS. Finally we review both pre-clinical and clinical studies involving intranasal delivery of biologics to the CNS. Copyright © 2011 Elsevier B.V. All rights reserved.

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Blood-brain barrier delivery.

William Pardridge (2007)

Neuropharmaceutics is the largest potential growth sector of the pharmaceutical industry. However, this growth is blocked by the problem of the blood-brain barrier (BBB). Essentially 100% of large-molecule drugs and >98% of small-molecule drugs do not cross the BBB. The BBB can be traversed because there are multiple endogenous transporters within this barrier. Therefore, brain drug development programs of the future need to be re-configured so that drugs are formulated to enable transport into the brain via endogenous BBB transporters.

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Convection-enhanced delivery of macromolecules in the brain.

R H Bobo, D W Laske, A Akbasak … (1994)

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.

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Author and article information

Journal

Journal ID (nlm-ta): Curr Med Chem

Journal ID (iso-abbrev): Curr. Med. Chem

Journal ID (publisher-id): CMC

Title: Current Medicinal Chemistry

Publisher: Bentham Science Publishers

ISSN (Print): 0929-8673

ISSN (Electronic): 1875-533X

Publication date (Print): March 2016

Publication date (Electronic): March 2016

Volume: 22

Issue: 9

Pages: 1177-1193

Affiliations

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201 USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201 USA; Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 USA; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 USA; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201 USA; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 USA; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201 USA

Author notes

[* ]Address correspondence to these authors at the Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201; E-mail: gwoodworth@ 123456smail.umaryland.edu , Departments of Neurosurgery and Pharmaceutical Sciences, University of Maryland, Baltimore, 655 W. Baltimore Street, Baltimore, MD 21201;, E-mail: akim@ 123456smail.umaryland.edu

[#]

These authors contributed equally.

Article

Publisher ID: CPD-22-1177

DOI: 10.2174/1381612822666151221150733

PMC ID: 4997920

PubMed ID: 26685681

SO-VID: 88d1214f-94fc-4775-b2a7-b62893f21526

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This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode ), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

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Bentham Science - Open Access

Most cited references 200

Intranasal delivery of biologics to the central nervous system.

Blood-brain barrier delivery.

Convection-enhanced delivery of macromolecules in the brain.

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