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Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
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| Authors: | Aaron G Filler Garth T Whiteside Mark Bacon Martyn Frederickson Franklyn A Howe Miri D Rabinowitz Alan J Sokoloff Terrence W Deacon Chris Abell Raj Munglani John R Griffiths B Anthony Bell Andrew ML Lever |
| Affiliation: | 1. Institute for Nerve Medicine, 2716 Ocean Park Blvd., Suite 3082, Santa Monica, CA, 90405, USA 12. Department of Organismic & Evolutionary Biology, Museum of Comparative Zoology, Harvard University, 26 Oxford Street, Cambridge, MA, 02138, USA 13. Department of Anthropology, Human Evolutionary Biology, Peabody Museum, Harvard University, 11 Divinity Ave., Cambridge, MA, 02138, USA 2. Department of Cell and Molecular Biology, St. George's Hospital Medical School, University of London, Cranmer Terrace, London, SW17 ORE, UK 3. Department of Neurosurgery, Atkinson Morley's Hospital, St. George's, University of London, 31 Copse Hill Road, London, SW20 ONE, UK 4. Division of Neurosurgery, UCLA School of Medicine, Center for Health Sciences, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA 5. SynGenix LTD, Babraham Hall, Babraham Research Campus, Cambridge, CB22 3AT, UK 6. Molecular Synthetics LTD, Babraham Hall, Babraham Research Campus, Cambridge, CB22 3AT, UK 7. Wyeth Research, Neuroscience Discovery Research, CN 8000 Princeton, NJ, 08543, USA 8. Spinal Research, Station Road, Bramley, Guildford, Surrey, GU5 0AZ, UK 18. Department of Chemistry, University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK 9. Astex Therapeutics, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK 10. Carmell Therapeutics Corporation, 10 South Tower, 320 E. North Ave., Pittsburgh, PA, 15212, USA 11. Department of Physiology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA 14. Department of Anthropology, University of California at Berkeley, 232 Kroeber Hall, Berkeley, CA, 94720, USA 17. Department of Anesthesia, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 2QQ, UK 16. Molecular Imaging, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge, CB2 ORE, UK 15. Neuroscience Unit, St. George's University of London, Cranmer Terrace, London, SW17 ORE, UK 19. Department of Internal Medicine, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 2QQ, UK |
| Abstract: | BackgroundTargeted 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.ResultsWe 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.ConclusionSpecific 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. |
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