New Enkephalin Nanomedicines for Pain Alleviation, Overcoming the Side Effects of Morphine

Over the last years, the nanomedicines has been recognized as a key element, capable of providing new and innovative medical solution to address unmet medical needs. More specifically, Squalene-based nanoparticles have opened exciting perspectives for drug delivery due to their biodegradability and their non-toxicity. In this study, it was shown for the first time, that the rapidly metabolized Leu-enkephalin (LENK) neuropeptide, once conjugated to the biocompatible lipid squalene (SQ) and formulated into nanoparticles, may become pharmacologically efficient. First, the resulting LENK-SQ bioconjugates were synthesized using different biocleavable chemical linkers, in order to modulate the LENK release from their formulation into nanoparticles (NPs). This nanoformulation led to new nanosystems exhibiting high drug loadings, allowed an efficient protection to LENK from early metabolism and conferred to the released neuropeptide a significant anti-hyperalgesic effect in a rat model of inflammatory pain which lasted longer than after treatment with morphine. A biodistribution study, as well as, the use of brain-permeant and -impermeant opioid receptor antagonists indicated that LENK-SQ NPs acted exclusively through peripherally located opioid receptors. This study showed that LENK-SQ bioconjugates may be beneficial in impacting the opioid crisis as these LENK-SQ NPs (i) exhibited higher affinity toward δ-opioid receptors versus μ-opioid receptors, (ii) showed exclusively peripheral activity (no BBB penetration) so no CNS addiction and (iii) took advantage of the inflammatory process to optimize drug concentrations at the site of injury.