posted on 2021-08-26, 18:13authored byAndrew
J. Kassick, Mariah Wu, Diego Luengas, Mohammad Ebqa’ai, L. P. Tharika Nirmani, Nestor Tomycz, Toby L. Nelson, Marco Pravetoni, Michael D. Raleigh, Saadyah Averick
The
mu opioid receptor antagonist naloxone has been a vital, long-standing
countermeasure in the ongoing battle against opioid use disorders
(OUD) and toxicity. However, due to its distinctive short elimination
half-life, naloxone has shown diminished efficacy in cases of synthetic
opioid poisoning as larger or repeated doses of the antidote have
been required to achieve adequate reversal of severe respiratory depression
and prevent episodes of renarcotization. This report describes the
synthesis, characterization, and in vivo evaluation
of a novel, nanoparticle-based naloxone formulation that provides
extended protection against the toxic effects of the powerful synthetic
opioid fentanyl. The strategy was predicated on a modified two-step
protocol involving the synthesis and subsequent nanoprecipitation
of a poly(lactic-co-glycolic acid) polymer scaffold
bearing a covalently linked naloxone chain end (drug loading ∼7%
w/w). Pharmacokinetic evaluation of the resulting covalently loaded
naloxone nanoparticles (cNLX-NP) revealed an elimination
half-life that was 34 times longer than high dose free naloxone (10
mg/kg) in male Sprague–Dawley rats. This enhancement was further
demonstrated by cNLX-NP in subsequent in
vivo studies affording protection against fentanyl-induced
respiratory depression and antinociception for up to 48 h following
a single intramuscular injection. These discoveries support further
investigation of cNLX-NP as a potential therapeutic
to reverse overdose and prevent renarcotization from fentanyl and
its potent analogs.