Tri-partite complex for axonal transport drug delivery achieves pharmacological effect
<p>Abstract</p> <p>Background</p> <p>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-viral...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-01-01
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| Series: | BMC Neuroscience |
| Online Access: | http://www.biomedcentral.com/1471-2202/11/8 |
| _version_ | 1811286638681128960 |
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| author | Frederickson Martyn Bacon Mark Whiteside Garth T Filler Aaron G Howe Franklyn A Rabinowitz Miri D Sokoloff Alan J Deacon Terrence W Abell Chris Munglani Raj Griffiths John R Bell B Anthony Lever Andrew ML |
| author_facet | Frederickson Martyn Bacon Mark Whiteside Garth T Filler Aaron G Howe Franklyn A Rabinowitz Miri D Sokoloff Alan J Deacon Terrence W Abell Chris Munglani Raj Griffiths John R Bell B Anthony Lever Andrew ML |
| author_sort | Frederickson Martyn |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p> |
| first_indexed | 2024-04-13T03:04:35Z |
| format | Article |
| id | doaj.art-cedead992ee744b0b679e2ba5ca2227a |
| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-04-13T03:04:35Z |
| publishDate | 2010-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj.art-cedead992ee744b0b679e2ba5ca2227a2022-12-22T03:05:19ZengBMCBMC Neuroscience1471-22022010-01-01111810.1186/1471-2202-11-8Tri-partite complex for axonal transport drug delivery achieves pharmacological effectFrederickson MartynBacon MarkWhiteside Garth TFiller Aaron GHowe Franklyn ARabinowitz Miri DSokoloff Alan JDeacon Terrence WAbell ChrisMunglani RajGriffiths John RBell B AnthonyLever Andrew ML<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p>http://www.biomedcentral.com/1471-2202/11/8 |
| spellingShingle | Frederickson Martyn Bacon Mark Whiteside Garth T Filler Aaron G Howe Franklyn A Rabinowitz Miri D Sokoloff Alan J Deacon Terrence W Abell Chris Munglani Raj Griffiths John R Bell B Anthony Lever Andrew ML Tri-partite complex for axonal transport drug delivery achieves pharmacological effect BMC Neuroscience |
| title | Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
| title_full | Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
| title_fullStr | Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
| title_full_unstemmed | Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
| title_short | Tri-partite complex for axonal transport drug delivery achieves pharmacological effect |
| title_sort | tri partite complex for axonal transport drug delivery achieves pharmacological effect |
| url | http://www.biomedcentral.com/1471-2202/11/8 |
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