Covalent Naloxone Nanoparticles for Next Generation Fentanyl Countermeasures

该中和R21项目专注于一种新型纳米粒药物输送的早期开发 FDA批准的纳洛酮持续和延长释放系统作为减少死亡的策略 芬太尼及其类似物过量。拟议的活动将包括优化纳洛酮纳米粒(NLX-NP)配方，并在暴露于芬太尼的临床前模型中测试其有效性。这个 近年来，由于芬太尼引发的大规模伤亡事件的幽灵 芬太尼或其类似物意外中毒的发生率。芬太尼是一种有效的疏水性小分子 一种分子，摄入少于2-3毫克的这种化合物即可引起中毒。海流 芬太尼中毒的对策是使用多剂量的Mu阿片受体 纳洛酮等拮抗剂。不幸的是，芬太尼的循环半衰期大于 解毒剂，由于芬太尼被脂肪组织吸收，作为药物洗脱储存库，增加了 再次麻醉的可能性。因此，芬太尼在纳洛酮服药后很长一段时间内仍可作为一种毒药。 代谢和排泄。为了更有效地逆转芬太尼及其衍生物的致命性，新的 解毒剂或解毒剂交付策略是必需的。这个R21项目测试了一种假设，即循环系统 通过使用一种新的药物输送系统，可以延长拮抗剂的半衰期，该系统包括 纳洛酮共价结合并结合到可生物降解纳米粒(NLX-NP)中。NLX-NP系统 允许FDA批准的治疗剂量的纳洛酮线性持续释放。AIM1将测试如何 纳米粒给药平台的组成对纳洛酮在大鼠体内的缓释有影响。 AIM2将测试NLX-NP是否会逆转或减少芬太尼诱导的药理作用，包括 对大鼠的呼吸抑制。NLX-NP将通过肌肉注射，这是 最能反映提供阿片类药物或其他化学品的对策的现场条件的行政当局 威胁。

This CounterAct R21 project focuses on early-stage development of a novel nanoparticle-based drug delivery system for sustained and extended release of the FDA-approved naloxone as a strategy to reduce fatal overdoses from fentanyl and its analogs. Proposed activities will include optimization of the naloxone-nanoparticle (NLX-NP) formulation and testing its efficacy in pre-clinical models of exposure to fentanyl. The specter of a fentanyl-based Mass Casualty Incident has been raised in recent years due to the increase incidence of accidental poisoning due to fentanyl or its analogs. Fentanyl is a potent hydrophobic small molecule that can cause poisoning upon ingestion of less than 2-3 mg of this compound. The current countermeasure for a fentanyl poisoning is the administration of multiple doses of a mu opioid receptor antagonist such as naloxone. Unfortunately, the circulatory half-life of fentanyl is greater than that of the antidote due to fentanyl’s absorption into adipose tissue, which act as a drug eluting reservoir increasing the likelihood of re-narcotization. Hence, fentanyl can still act as a poison long after the naloxone has been metabolized and excreted. To more effectively reverse the lethality of fentanyl and its derivatives, new antidotes or antidote delivery strategies are required. This R21 project tests the hypothesis that the circulatory half-life of an antagonist can be increased through the use of a novel drug delivery system consisting of naloxone covalently bound and incorporated into biodegradable nanoparticles (NLX-NP). The NLX-NP system allows for the linear sustained release of therapeutic doses of the FDA-approved naloxone. AIM1 will test how the composition of the nanoparticle-based delivery platform impacts the sustained release of naloxone in rats. AIM2 will test whether the NLX-NP will reverse or reduce fentanyl-induced pharmacological effects, including respiratory depression in rats. The NLX-NP will be delivered intramuscularly, which is the route of administration that best reflects field conditions for delivery of countermeasures to opioids or other chemical threats.