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Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.

Filler, AG; Whiteside, GT; Bacon, M; Frederickson, M; Howe, FA; Rabinowitz, MD; Sokoloff, AJ; Deacon, TW; Abell, C; Munglani, R; et al. Filler, AG; Whiteside, GT; Bacon, M; Frederickson, M; Howe, FA; Rabinowitz, MD; Sokoloff, AJ; Deacon, TW; Abell, C; Munglani, R; Griffiths, JR; Bell, BA; Lever, AM (2010) Tri-partite complex for axonal transport drug delivery achieves pharmacological effect. BMC NEUROSCIENCE, 11 (8). ISSN 1471-2202 https://doi.org/10.1186/1471-2202-11-8
SGUL Authors: Bell, Bryan Anthony Howe, Franklyn Arron

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Abstract

BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.

Item Type: Article
Additional Information: PubMed ID: 20085661 © 2010 Filler et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Amines, Analgesics, Animals, Axonal Transport, Cell Line, Cells, Cultured, Cricetinae, Cyclohexanecarboxylic Acids, Dextrans, Dose-Response Relationship, Drug, Drug Delivery Systems, Half-Life, Macaca fascicularis, Models, Neurological, Nanoparticles, Nerve Growth Factor, Neurons, Pain, Polymers, Rabbits, Rats, Rats, Sprague-Dawley, Wheat Germ Agglutinins, gamma-Aminobutyric Acid, Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, MAGNETIC-RESONANCE NEUROGRAPHY, PERIPHERAL NERVOUS-SYSTEM, RAT SYMPATHETIC NEURONS, WHEAT-GERM-AGGLUTININ, HORSERADISH-PEROXIDASE, RETROGRADE TRANSPORT, GROWTH-FACTOR, ANTEROGRADE TRANSPORT, EPITOPE LIBRARY, SENSORY NEURONS
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Neuroscience (INCCNS)
Journal or Publication Title: BMC NEUROSCIENCE
ISSN: 1471-2202
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Dates:
DateEvent
20 January 2010Published
Web of Science ID: WOS:000275373800001
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URI: http://openaccess.sgul.ac.uk/id/eprint/993
Publisher's version: https://doi.org/10.1186/1471-2202-11-8

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