INTRODUCTION:
Pharmacological treatment of nervous tissue pathology is often hindered because the precise site of pathology cannot be reached with adequate levels of pharmacological agents without eliciting unwanted side effects. Delivery of pharmaceutical agents directly to selected target sites within the nervous system can avoid undesired systemic toxicity as well as inappropriate side effects in non-target neural tissue.
METHODS:
We constructed a novel multivalent complex comprising of an axonal transport facilitator (ATF) conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. This complex was configured to deliver the anticonvulsant, gabapentin to selected dorsal root ganglia by retrograde axonal transport after injection into peripheral tissue innervated by the target nerves. The efficacy of this agent was evaluated in vivo using the chronic constriction injury model of neuropathic pain. Paw withdrawal latency (PWL) to thermal stimuli was measured in the ipsilateral and contralateral limbs.
RESULTS:
A single injection of ATF drug complex (total gabapentin dose; 75mg/200g rat) caused a statistically significant reduction of mean hyperalgesia (by 50%) lasting up to 4 days. No similar effect was seen in control groups treated with either free drug or drug complex lacking the ATF. To achieve such an effect by systemic delivery would require a 300-fold increase in dosage. Tracer studies confirm drug delivered by axonal transport achieves concentrations in targeted nerve cell bodies many times greater that in non-targeted tissues.
CONCLUSIONS:
Axonal transport can deliver therapeutically relevant concentrations of drug, drastically reducing the total dosage required for therapeutic effect and unwanted side effects.
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