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Covalent Naloxone Nanoparticles for Next Generation Fentanyl Countermeasures

用于下一代芬太尼对策的共价纳洛酮纳米颗粒

基本信息

批准号：
10153748
负责人：
Saadyah Averick
金额：
$ 23.53万
依托单位：
ALLEGHENY-SINGER RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153748
关键词：
Acute Adipose tissue Affinity Antidotes Behavioral Biological Blood - brain barrier anatomy Bradycardia Clinical Research Dangerousness Data Development Devices Dose Drug Delivery Systems Drug Kinetics Ensure Exposure to FDA approved Fentanyl Formulation Goals Half-Life Human Hydrophobicity In Vitro Incidence Ingestion Injections Intramuscular Intravenous Law Enforcement Lead Medical Military Personnel Monitor Naloxone Narcan Opioid Opioid Antagonist Opioid agonist Overdose Pharmaceutical Preparations Pharmacology Plasma Poison Poisoning Polymers Pre-Clinical Model Process Protocols documentation Rattus Recovery Risk Route Serum Site Symptoms System Testing Therapeutic Time Toxic effect United States Dept. of Health and Human Services Ventilatory Depression Weight absorption analog base biomaterial compatibility chemical threat efficacy testing fentanyl overdose in vivo interest liver metabolism mass casualty mu opioid receptors nanoparticle next generation novel novel therapeutics opioid overdose opioid use disorder particle preclinical study prevent programs small molecule subcutaneous synthetic opioid

项目摘要

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.

该CounterAct R21项目的重点是基于纳米颗粒的新型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致命性过量使用芬太尼及其类似物拟议的活动将包括优化纳洛酮纳米颗粒（NLX-NP）制剂，并在暴露于芬太尼的临床前模型中测试其疗效。的近年来，由于芬太尼的增加，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这种分子在摄入少于2 - 3毫克这种化合物时可引起中毒。当前芬太尼中毒的对策是给予多剂量的μ阿片受体拮抗剂如纳洛酮。不幸的是，芬太尼的循环半衰期大于由于芬太尼被吸收到脂肪组织中，脂肪组织作为药物洗脱储库，增加了重新麻醉的可能性。因此，芬太尼仍然可以作为一种毒药后，纳洛酮已经很长时间代谢和排泄。为了更有效地扭转芬太尼及其衍生物的致命性，需要解毒剂或解毒剂递送策略。这个R21项目测试了循环系统拮抗剂的半衰期可以通过使用新的药物递送系统来增加纳洛酮共价结合并掺入可生物降解的纳米颗粒（NLX-NP）中。NLX-NP系统允许治疗剂量的FDA批准的纳洛酮的线性持续释放。AIM1将测试如何基于纳米颗粒的递送平台的组成影响纳洛酮在大鼠中的持续释放。 AIM2将测试NLX-NP是否会逆转或减少芬太尼诱导的药理学作用，包括大鼠呼吸抑制。NLX-NP将通过肌内给药，这是给药途径。最能反映对阿片类药物或其他化学品采取对策的实地条件的行政管理威胁