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<p>This study investigates the potential of a novel nanomedicine approach relying on squalene nanoparticles of endogenous enkephalinase inhibitors (EEI) – opiorphin (OPN) and STR-324 – to alleviate pain by potentiating the action of enkephalins in vivo, in a model of acute inflammatory pain. A library of squalene-based EEI prodrugs was synthesized. These prodrugs were unable to self-assemble into nanoparticles, in contrast to the other squalenoylated prodrugs, probably due to their high hydrophilicity. By incorporating either squalenic acid (SQ) or enkephalin-squalene (LENK-SQ) prodrug as adjuvants with strong self-assembling properties, we successfully formulated nanoparticles of STR- or OPN-SQ (EEI-SQ NPs) and performed their physicochemical characterization. The analgesic efficacy of these formulations was evaluated in a carrageenan-induced pain model using the Hargreaves test to assess hyperalgesia. Nevertheless, the intravenous administration of EEI-SQ NPs caused systemic toxicity which was investigated through in vitro incubation assays. It was discovered that EEI-SQ bioconjugates exhibited strong interactions with divalent anions in physiological media, leading to nanoparticles aggregation, which was further confirmed in silico by molecular dynamics simulations. EEI-SQ NPs administered subcutaneously successfully enhanced the anti-hyperalgesic effect of LENK-SQ NPs. However, it was considered as not relevant enough regarding the observed local toxicity.</p> Graphical abstract <p></p>

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Combining Leu-enkephalin nanomedicines with enkephalinase inhibitors: a promising painkiller strategy?

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Lucas Prades,
  • Hadjer Hazam,
  • Frédéric Gobeaux,
  • Semen Yesylevskyy,
  • Christophe Ramseyer,
  • Luigi Ranieri,
  • Scander Loukil,
  • Catherine Cailleau,
  • Philippe Sitbon,
  • Patrick Couvreur,
  • Sinda Lepetre-Mouelhi

摘要

This study investigates the potential of a novel nanomedicine approach relying on squalene nanoparticles of endogenous enkephalinase inhibitors (EEI) – opiorphin (OPN) and STR-324 – to alleviate pain by potentiating the action of enkephalins in vivo, in a model of acute inflammatory pain. A library of squalene-based EEI prodrugs was synthesized. These prodrugs were unable to self-assemble into nanoparticles, in contrast to the other squalenoylated prodrugs, probably due to their high hydrophilicity. By incorporating either squalenic acid (SQ) or enkephalin-squalene (LENK-SQ) prodrug as adjuvants with strong self-assembling properties, we successfully formulated nanoparticles of STR- or OPN-SQ (EEI-SQ NPs) and performed their physicochemical characterization. The analgesic efficacy of these formulations was evaluated in a carrageenan-induced pain model using the Hargreaves test to assess hyperalgesia. Nevertheless, the intravenous administration of EEI-SQ NPs caused systemic toxicity which was investigated through in vitro incubation assays. It was discovered that EEI-SQ bioconjugates exhibited strong interactions with divalent anions in physiological media, leading to nanoparticles aggregation, which was further confirmed in silico by molecular dynamics simulations. EEI-SQ NPs administered subcutaneously successfully enhanced the anti-hyperalgesic effect of LENK-SQ NPs. However, it was considered as not relevant enough regarding the observed local toxicity.

Graphical abstract