Apamin-Mediated Actively Targeted Drug Delivery for Treatment of Spinal Cord Injury: More Than Just a Concept

Abstract

Faced with the complex medical challenge presented by spinal cord injuries (SCI) and considering the lack of any available curative therapy, the development of a novel method of delivering existing drugs or candidate agents can be perceived to be as important as the development of new therapeutic molecules. By combining three ingredients currently in clinical use or undergoing testing, we have designed a central nervous system targeted delivery system based on apamin-modified polymeric micelles (APM). Apamin, one of the major components of honey bee venom, serves as the targeting moiety, poly(ethylene glycol) (PEG) distearoylphosphatidylethanolamine (DSPE) serves as the drug-loaded material, and curcumin is used as the therapeutic agent. Apamin was conjugated with NHS (N-hydroxysuccinimide)-PEG-DSPE in a site-specific manner, and APM were prepared by a thin-film hydration method. A formulation comprising 0.5 mol % targeting ligand with 50 nm particle size showed strong targeting efficiency in vivo and was evaluated in pharmacodynamic assays. A 7-day treatment by daily intravenous administration of low doses of APM (corresponding to 5 mg/kg of curcumin) was performed. Significantly enhanced recovery and prolonged survival was found in the SCI mouse model, as compared to sham-treated groups, with no apparent toxicity. A single dose of apamin-conjugated polymers was about 700-fold lower than the LD50 amount, suggesting that APM and apamin have potential for clinical applications as spinal cord targeting ligand for delivery of agents in treatment of diseases of the central nervous system.

Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

“…89 In addition to the aforementioned receptors, many other pathways have been explored in an attempt to increase brain delivery efficiency and selectivity. The widespread occurrence of some ion channels in the CNS, as well as their intracellular traffic and recycling ability, have inspired several shuttles, comprising RVG29, RDPs, 90,91 KC2S, 92 L CDX, 93 D CDX, 94 apamin, 95,96 and MiniAp-4. 97 By contrast, the endogenous peptide GSH was identified as a BBB shuttle following from its reported capacity to reach the brain through a saturable and specific mechanism.…”

MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

“…In particular, the bicyclic peptide apamin, found in bee venom, crosses the BBB and blocks calcium‐mediated potassium channels 4. Despite the proven CNS‐targeting capacity of apamin,5 the extended application of this molecule has been limited by its toxicity, high immunogenicity,6 and relatively complex structure. Two years ago, we reported that the replacement of arginines by ornithines yielded a non‐toxic apamin analogue that is able to cross a tight monolayer of bovine endothelial cells mimicking the BBB 7.…”

Recent advances in synthetic polymer based hydrogels for spinal cord repair

“…Similarly, drugloaded nano-carriers (e.g. biodegradable nanoparticles), that have been shown to selectively target the lesion site and to bring substantial improvements [52], still present a limited efficiency that is frequently due to inadequate drug release from the nanoparticles or the difficulty to cross the BSCB [53]. As for local delivery through intrathecal injection, it is not really satisfactory because of rapid clearance due to cerebrospinal fluid flow in the intrathecal space, and the necessity of repeated doses, which poses the problem of recurrent infections.…”