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.

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共价负载纳洛酮纳米颗粒作为阿片类药物中毒的长效医疗对策

mu 阿片受体拮抗剂纳洛酮一直是对抗阿片类药物使用障碍 (OUD) 和毒性的持续斗争中至关重要的长期对策。然而，由于其独特的短消除半衰期，纳洛酮在合成阿片类药物中毒的情况下显示出疗效减弱，因为需要更大或重复剂量的解毒剂才能充分逆转严重呼吸抑制并防止再次麻醉发作。本报告描述了一种新型纳米颗粒纳洛酮制剂的合成、表征和体内评估，该制剂可针对强效合成阿片类芬太尼的毒性作用提供长期保护。该策略基于修改后的两步方案，涉及聚乳酸-乙醇酸共聚物聚合物支架的合成和随后的纳米沉淀，该支架具有共价连接的纳洛酮链端（药物负载量〜7％w/w）。对所得共价负载纳洛酮纳米颗粒 ( c NLX-NP) 的药代动力学评估显示，在雄性 Sprague-Dawley 大鼠中，消除半衰期比高剂量游离纳洛酮 (10 mg/kg) 长 34 倍。c NLX-NP 在随后的体内研究中进一步证明了这种增强作用，在单次肌肉注射后长达 48 小时内可提供针对芬太尼诱导的呼吸抑制和镇痛的保护作用。这些发现支持进一步研究c NLX-NP 作为一种潜在的治疗方法，以逆转芬太尼及其强效类似物的过量用药并防止再麻醉。