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: 9912595
• 负责人: Babak Esmaeli-Azad
• 金额: $ 25.4万
• 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 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912595
• 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; off-patent; 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

抽象的 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方法 阿片类药物过量可以补充和补偿纳络酮的不足， 使用以阿片类药物为目标的仿生“纳米海绵”，吸收过量的阿片类药物 身体。 （注意：如果这个概念验证在这里成功，该方法可能会针对其他 滥用药物。）这些直径为 100 nm 的纳米球被称为“NarcoBondTM” 来自模拟脂质双层的胆固醇和合成胆碱磷脂的混合物 细胞膜。其多功能表面显示出优化的人体膜环境 从以下来源分离出的蛋白质：a) 红细胞，可延长外周血液和循环中的半衰期，b) 神经元增加对阿片受体的结合亲和力，&c) 纯化的 Mu 阿片受体结合 流通中的阿片类药物。 NarcoBond 的天然阿片受体库广泛结合和 从组织细胞的微环境中捕获阿片类药物，并将导致 通过迅速降低过量药物的浓度而产生拮抗药理作用 阿片类药物。 意义。每 15 分钟一班在美国，有人因过量服用阿片类药物而死亡。1 纳洛酮，一种 阿片受体拮抗剂，是迄今为止唯一一种针对阿片类药物过量的救生治疗方法 其急性逆转呼吸抑制的能力。3 然而，其药效作用 纳洛酮的持续时间比除最短效阿片类药物外的所有药物都要短；3-9 纳洛酮的消除半衰期与吗啡相似 (60–90')9，它被重新分配 更快地从大脑中消失。3因此，患者可能会在术后再次麻醉。 由于外周血中持续存在阿片类药物，因此需要进行纳洛酮治疗。全文 开发，NarcoBond 提供了更广泛的替代方案，具有成本效益且更持久 净化外周血液中的阿片类药物，降低再次麻醉的风险，以及 协助挽救生命，逆转药物过量引起的呼吸抑制。尽管 提示急性戒断综合征（AWS）始终是快速阿片受体阻断的一个风险， 如果没有重新麻醉的复发性呼吸抑制的严重风险，临床医生将 有更多时间通过逐步断奶方案进行干预以避免 AWS。此外， NarcoBond 具有广泛的能力，可以缓解所有阿片类药物，包括高效合成阿片类药物 丙烯酰芬太尼（即“纳洛酮抗性”化学威胁剂），解决了未满足的需求 恐怖主义和人质劫持情况下的医疗对策。8,11