NarcoBond: Opioid Targeted Biomimetic Nanosponges for Treatment of Opioid Overdose

NarcoBond：阿片类药物靶向仿生纳米海绵用于治疗阿片类药物过量

• 批准号: 10179237
• 负责人: Babak Esmaeli-Azad
• 金额: $ 9.59万
• 依托单位: CIBOTS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179237
• 关键词: ARNT gene; Acute; Address; Affinity; Binding; Biodistribution; Biological Assay; Biomimetics; Blood; Blood Circulation; Brain; Caliber; Cell membrane; Cells; Cellular Assay; Cholesterol; Choline; Clinical; Codeine; Complement; Derivation procedure; Development; Erythrocytes; Fatty acid glycerol esters; Fentanyl; Half-Life; Hostage; Human; Hydrocodone; In Vitro; Intravenous; Legal patent; Life; Lipid Bilayers; Liquid substance; Liver; Lymph; Membrane; Membrane Proteins; Methadone; Morphine; Mus; Naloxone; Nanosphere; Neurons; Nociception; Nociceptors; Opioid; Opioid Antagonist; Opioid Receptor; Opioid Receptor Binding; Overdose; Oxycodone; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phospholipids; Protocols documentation; Recording of previous events; Recurrence; Resistance; Risk; Savings; Serum; Solid; Substance Withdrawal Syndrome; Surface; Terrorism; Time; Tissues; Translating; Urine; Vaccination; Ventilatory Depression; Weaning; base; chemical threat; clinical application; cost effective; drug of abuse; in vivo; induced pluripotent stem cell; innovation; medical countermeasure; mu opioid receptors; novel; novel strategies; opioid epidemic; opioid injection; opioid misuse; opioid overdose; opioid use; peripheral blood; screening; tool

Abstract We propose to develop a broad acute/sub-acute opioid drug detoxifying treatment for opioid overdose that can complement & compensate for the deficiencies in nalaxone, using opioid-targeted biomimetic “nanosponges” that absorb overdosed opioids in the body. (Note: if this proof-of-concept is successful here, the approach may be tailored to other drugs-of-abuse.) Called “NarcoBondTM” these 100 nm diameter nanospheres are assembled from a mixture of cholesterol & synthetic choline-based phospholipids that mimic the lipid bilayer cell membranes. Its multifunctional surface displays an optimized milieu of human membrane proteins isolated from: a) erythrocytes to increase half-life in peripheral blood & circulation, b) neurons to increase binding affinity for opioid receptor, & c) purified Mu opioid receptors to bind opioids in circulation. The NarcoBond's repertoire of native opioid receptors broadly binds & captures opioids from microenvironmental niches of cells in tissues & will result in an antagonistic pharmacological effect by rapidly reducing the concentration of the overdosed opioid. Significance. Every 15 min. in the US, a person dies after overdosing on opioids.1 Naloxone, an opioid receptor antagonist, is, to date, the only life-saving treatment for opioid overdose based on its ability to reverse respiratory depression acutely.3 Yet the pharmacodynamic actions of naloxone last for a briefer period than all but the most short acting opioids;3-9 although the elimination half life of naloxone is similar to that of morphine (60–90')9 it is redistributed away from the brain more rapidly.3 Consequently, the patients may become renarcotised after naloxone treatment due to the continued presence of opioids in peripheral blood. In full development, NarcoBond offers a more broad alternative for cost effective & longer lasting means to cleanse the peripheral blood of opioids, reducing the risk of renarcotisation, & assisting in the life-saving reversal of overdose-induced respiratory depression. While prompting acute withdrawal syndrome (AWS) is always a risk in rapid opioid receptor blockade, without renarcotisation's acute risk of recurrent respiratory depression, clinicians will have more time to intervene with gradual weaning protocols to avoid AWS. In addition, NarcoBond's broad capability to mitigate against all opioids including highly potent synthetic acrylfentanyl (i.e., “naloxone resistant” chemical threat agents), addresses unmet need(s) for medical countermeasures in terrorism & hostage scenarios.8,11

摘要 我们建议开发一种广泛的急性/亚急性阿片类药物解毒治疗， 阿片类药物过量，可以补充和补偿纳洛酮的不足， 使用阿片类药物靶向的仿生“纳米海绵”， 身体(Note：如果这一概念验证在这里取得成功，该方法可以针对其他 滥用药物。）被称为“NarcoBondTM”的这些100纳米直径的纳米球组装 从胆固醇和合成胆碱基磷脂的混合物， 细胞膜它的多功能表面显示了优化的人体膜环境 分离自以下的蛋白质：a）红细胞，以增加外周血和循环中的半衰期，B） c）纯化的Mu阿片受体，以结合 阿片类药物在循环。NarcoBond的天然阿片受体库广泛结合& 从组织细胞的微环境小生境中捕获阿片类药物， 拮抗药理作用，通过快速降低过量的 阿片类药物 意义在美国，每15分钟就有一个人在过量服用阿片类药物后死亡。 阿片受体拮抗剂，是迄今为止，唯一的挽救生命的治疗阿片类药物过量的基础 其逆转急性呼吸抑制的能力。3然而， 纳洛酮持续的时间比除最短作用的阿片类药物外的所有药物都要短;3-9，尽管 纳洛酮的消除半衰期与吗啡相似（60- 90 '）9，它被重新分布 3因此，患者可能会在术后发生再神经病变。 纳洛酮治疗由于阿片类药物在外周血中的持续存在。足额 发展，NarcoBond提供了一个更广泛的替代成本效益和更持久的 清除外周血中阿片类药物的方法，降低再麻醉的风险， 帮助挽救过量引起的呼吸抑制的逆转。而 促使急性戒断综合征（AWS）始终是快速阿片受体阻断的风险， 没有再麻醉的复发性呼吸抑制的急性风险，临床医生将 有更多的时间来干预逐步断奶协议，以避免AWS。此外，本发明还提供了一种方法， NarcoBond的广泛能力，以减轻对所有阿片类药物，包括高效合成 丙烯酰芬太尼（即，“耐纳洛酮”化学威胁剂），解决了 恐怖主义和人质劫持事件中的医疗对策8，11