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

摘要 我们建议开发一种广泛的急性/亚急性阿片类药物戒毒治疗 阿片类药物过量，可以补充和弥补纳洛酮的不足， 使用阿片靶向的仿生“纳米棒”吸收过量的阿片类药物 尸体。(注意：如果此概念验证在这里成功，则该方法可能适用于其他 滥用毒品问题。)这些直径为100 nm的纳米球被称为“NarcoBondTM”。 从胆固醇和模拟脂质双层的合成胆碱基磷脂的混合物中 细胞膜。它的多功能表面显示了优化的人膜环境 从红细胞中分离出的蛋白质：a)增加外周血液和循环中的半衰期，b) 神经元增加与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。纳可邦德的天然阿片受体曲目广泛结合& 从组织细胞的微环境中捕获阿片类药物&将导致 快速降低过量用药浓度的拮抗药理作用 阿片类药物。 意义重大。每隔15分钟。在美国，一个人在过量服用阿片类药物后死亡。1纳洛酮 阿片受体拮抗剂是迄今为止阿片类药物过量的唯一挽救生命的治疗方法 对其急性逆转呼吸抑制的能力。3但其药效学作用 纳洛酮的持续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类似于吗啡的消除半衰期(60-90‘)。 更快地从大脑中排出。3因此，患者可能在 纳洛酮治疗由于外周血中持续存在阿片类药物。全部 开发，NarcoBond为经济高效和更持久的发展提供了更广泛的选择 清除外周血中阿片类药物的手段，降低再电离化的风险 协助扭转过量用药引起的呼吸抑制的救命作用。而当 提示急性戒断综合征(AWS)总是阿片受体快速阻断的风险， 如果没有肾炎复发呼吸抑制的急性风险，临床医生将 有更多的时间通过逐步断奶方案进行干预，以避免AWS。此外, 纳可邦德广泛的能力，以缓解所有阿片类药物，包括高度有效的合成 丙烯芬太尼(即耐纳洛酮的化学威胁剂)，满足未满足的需求(S) 恐怖主义和人质事件中的医学对策8，11