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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, Griffiths JR, Bell BA, Lever AM - BMC Neurosci (2010)

Bottom Line: 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.The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Nerve Medicine, 2716 Ocean Park Blvd,, Suite 3082, Santa Monica, CA 90405, USA. afiller@nervemed.com

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.

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Intra-axonal location of transported agents. (a) Electron micrograph of rabbit tibial nerve four days after injection of the gastrocnemius muscle with ferrite-WGA tracer. (b) magnified view of a vesicle seen in (a) to 195,000×. (ly) lysosomal vesicle, (fp) small particles transporting on microtubules (mi), (ep) larger particles in vesicles.
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Figure 6: Intra-axonal location of transported agents. (a) Electron micrograph of rabbit tibial nerve four days after injection of the gastrocnemius muscle with ferrite-WGA tracer. (b) magnified view of a vesicle seen in (a) to 195,000×. (ly) lysosomal vesicle, (fp) small particles transporting on microtubules (mi), (ep) larger particles in vesicles.

Mentions: Electron microscopy showed appropriately sized ferrites within the axon, more than three centimeters from the WGA-dextran-Fe injection site (Figure 6). The appearance of the ferrites in endosomes was similar to what has been seen in studies of similar agents in other tissues [31], but in this case the particles were restricted to the axonal stream. The autoradiographic studies demonstrated sciatic nerve radioactivity and so provided similar evidence that the magnetite containing particles were transported in nerves.


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, Griffiths JR, Bell BA, Lever AM - BMC Neurosci (2010)

Intra-axonal location of transported agents. (a) Electron micrograph of rabbit tibial nerve four days after injection of the gastrocnemius muscle with ferrite-WGA tracer. (b) magnified view of a vesicle seen in (a) to 195,000×. (ly) lysosomal vesicle, (fp) small particles transporting on microtubules (mi), (ep) larger particles in vesicles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837052&req=5

Figure 6: Intra-axonal location of transported agents. (a) Electron micrograph of rabbit tibial nerve four days after injection of the gastrocnemius muscle with ferrite-WGA tracer. (b) magnified view of a vesicle seen in (a) to 195,000×. (ly) lysosomal vesicle, (fp) small particles transporting on microtubules (mi), (ep) larger particles in vesicles.
Mentions: Electron microscopy showed appropriately sized ferrites within the axon, more than three centimeters from the WGA-dextran-Fe injection site (Figure 6). The appearance of the ferrites in endosomes was similar to what has been seen in studies of similar agents in other tissues [31], but in this case the particles were restricted to the axonal stream. The autoradiographic studies demonstrated sciatic nerve radioactivity and so provided similar evidence that the magnetite containing particles were transported in nerves.

Bottom Line: 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.The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Nerve Medicine, 2716 Ocean Park Blvd,, Suite 3082, Santa Monica, CA 90405, USA. afiller@nervemed.com

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.

Show MeSH
Related in: MedlinePlus