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.

CounterAct R21 项目专注于新型纳米颗粒药物输送的早期开发持续和延长释放 FDA 批准的纳洛酮的系统，作为减少致命性的策略拟议的活动将包括优化纳洛酮纳米颗粒（NLX-NP）配方并测试其在芬太尼暴露的临床前模型中的功效。近年来，由于芬太尼类药物造成的大规模伤亡事件的增加，人们对此类事件的担忧不断增加。芬太尼或其类似物是一种强效疏水性小剂，导致意外中毒的发生率较高。摄入少于 2-3 毫克该化合物即可引起中毒的分子。芬太尼中毒的对策是给予多剂量的 mu 阿片受体不幸的是，芬太尼的循环半衰期比纳洛酮长。由于芬太尼吸收到脂肪组织中而成为解毒剂，脂肪组织充当药物洗脱库，增加因此，在纳洛酮被麻醉很长时间后，芬太尼仍然可以起到毒药的作用。更有效地逆转芬太尼及其衍生物的致死性。需要解毒剂或解毒剂输送策略。该 R21 项目测试了循环系统的假设。拮抗剂的半衰期可以通过使用由以下组成的新型药物递送系统来延长：纳洛酮共价结合并掺入可生物降解的纳米颗粒（NLX-NP）中。允许线性持续释放 FDA 批准的纳洛酮 AIM1 将如何测试。基于纳米颗粒的递送平台的成分影响纳洛酮在大鼠体内的持续释放。 AIM2将测试NLX-NP是否会逆转或减少芬太尼引起的药理作用，包括 NLX-NP 将通过肌肉注射的方式抑制大鼠的呼吸。最能反映针对阿片类药物或其他化学品采取对策的现场条件的管理威胁。