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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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Related in: MedlinePlus

T2 relaxivity of hydroxide free magnetite preparations. T2 relaxivity curves for polyacrylamide "tissue" gels polymerized with uniform distributions of various dextran coated magnetite particle preparations. Relaxivity is compared with the concentration of particles in the each gel preparation as assessed by ferrozine assay of iron content after the imaging. 1/T2 was measured in a 4.7Tesla Sisco MR spectrometer. At concentrations comparable to what was achieved in nerve by axonal transport, a T2 below 30 milliseconds would be expected for any of these particle preparations. D10 = 10,000 MW dextran coating, D40 - 40,000 MW, D70 - 70,000 MW, Mgn = magnetite, WGA is wheat germ agglutinin, Seph II - sepharose separated to reduce contamination of magnetite by non-superparamagnetic ferrites.
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Figure 7: T2 relaxivity of hydroxide free magnetite preparations. T2 relaxivity curves for polyacrylamide "tissue" gels polymerized with uniform distributions of various dextran coated magnetite particle preparations. Relaxivity is compared with the concentration of particles in the each gel preparation as assessed by ferrozine assay of iron content after the imaging. 1/T2 was measured in a 4.7Tesla Sisco MR spectrometer. At concentrations comparable to what was achieved in nerve by axonal transport, a T2 below 30 milliseconds would be expected for any of these particle preparations. D10 = 10,000 MW dextran coating, D40 - 40,000 MW, D70 - 70,000 MW, Mgn = magnetite, WGA is wheat germ agglutinin, Seph II - sepharose separated to reduce contamination of magnetite by non-superparamagnetic ferrites.

Mentions: The relaxivity experiments (Figure 7) taken together with distribution studies showed that the concentration of magnetite delivered to the axon by the tripartite was sufficient to affect the T2 relaxation rate of nerve. The observation of a decrease of T2 relaxation time in nerves transporting superparamagnetic nanoparticles in both the micro-MRI nerve channel studies (Figure 8) and in the high resolution MRI experiments (Figure 9) confirmed that the carrier particles were not degraded. Any hydrolysis of the sub-domain sized particles would have eradicated their superparamagnetic effect on T2 relaxation time in nerve as transport progressed. The relaxivity effect far exceeded that which would result from free iron or ferritin at the doses administered.


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)

T2 relaxivity of hydroxide free magnetite preparations. T2 relaxivity curves for polyacrylamide "tissue" gels polymerized with uniform distributions of various dextran coated magnetite particle preparations. Relaxivity is compared with the concentration of particles in the each gel preparation as assessed by ferrozine assay of iron content after the imaging. 1/T2 was measured in a 4.7Tesla Sisco MR spectrometer. At concentrations comparable to what was achieved in nerve by axonal transport, a T2 below 30 milliseconds would be expected for any of these particle preparations. D10 = 10,000 MW dextran coating, D40 - 40,000 MW, D70 - 70,000 MW, Mgn = magnetite, WGA is wheat germ agglutinin, Seph II - sepharose separated to reduce contamination of magnetite by non-superparamagnetic ferrites.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: T2 relaxivity of hydroxide free magnetite preparations. T2 relaxivity curves for polyacrylamide "tissue" gels polymerized with uniform distributions of various dextran coated magnetite particle preparations. Relaxivity is compared with the concentration of particles in the each gel preparation as assessed by ferrozine assay of iron content after the imaging. 1/T2 was measured in a 4.7Tesla Sisco MR spectrometer. At concentrations comparable to what was achieved in nerve by axonal transport, a T2 below 30 milliseconds would be expected for any of these particle preparations. D10 = 10,000 MW dextran coating, D40 - 40,000 MW, D70 - 70,000 MW, Mgn = magnetite, WGA is wheat germ agglutinin, Seph II - sepharose separated to reduce contamination of magnetite by non-superparamagnetic ferrites.
Mentions: The relaxivity experiments (Figure 7) taken together with distribution studies showed that the concentration of magnetite delivered to the axon by the tripartite was sufficient to affect the T2 relaxation rate of nerve. The observation of a decrease of T2 relaxation time in nerves transporting superparamagnetic nanoparticles in both the micro-MRI nerve channel studies (Figure 8) and in the high resolution MRI experiments (Figure 9) confirmed that the carrier particles were not degraded. Any hydrolysis of the sub-domain sized particles would have eradicated their superparamagnetic effect on T2 relaxation time in nerve as transport progressed. The relaxivity effect far exceeded that which would result from free iron or ferritin at the doses administered.

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