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

基本信息

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
项目类别：
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

项目摘要

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（注意：如果这个概念验证在这里成功，则该方法可以针对其他方法进行定制）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 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。在美国，每 15 分钟就有一人因服用阿片类药物过量而死亡。1 纳洛酮，一种阿片受体拮抗剂，是迄今为止唯一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，纳洛酮的持续时间比除最短效阿片类药物以外的所有阿片类药物都要短；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排出。3 检查后，患者可能会再次麻醉由于外周血中持续存在阿片类药物而进行纳洛酮治疗。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。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反复呼吸抑制的急性风险，居住者将有更多时间进行逐步断奶方案以避免 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