A novel drug delivery system for the prevention and rescue of fentanyl and other opioid overdoses

阿片类药物有显著的不良反应，突出表现为大量的阿片类药物使用障碍患者 (OUD)以及美国和其他地方服药过量死亡人数的增加。在短短12个月内 截至2021年11月，超过10.7万美国人死于药物过量。其中约66%的人 死亡涉及非法合成阿片类药物，如芬太尼(效力约为海洛因的50倍，100 阿片类药物(药效是吗啡的几倍)，是当今阿片类药物流行的主要驱动力。许多阿片类药物 过量死亡归因于芬太尼与其他非法药物的混合，如海洛因，可卡因和 冰毒。芬太尼的潜在致死剂量约为2毫克，特别危险 对于对阿片类药物没有耐受性的阿片类药物天真的人。高中生服药过量死亡情况分析 自2019年以来，美国人的人数翻了一番以上，这被归因于假药(例如，Xanax， Perdicet，Adderall)中加入了致死量的芬太尼。可悲的是，许多吸毒者经常服用这种致命的药物 不知不觉中。不幸的是，这个毁灭性的故事没有一个圆满的结局，也没有简单的解决方案。 关于合成阿片类药物的问题。我国对高效芬太尼武器化的脆弱性 类似物，如卡芬太尼(效力是芬太尼的20倍)，不仅对 不仅对平民，而且对急救人员、执法人员和军方。持续时间相对较短 阿片受体拮抗剂纳洛酮和纳美芬的作用时间(DOA)对其 对抗芬太尼过量的疗效。很难想象纳洛酮和纳美芬是如何部署的 在涉及合成阿片类药物的大规模伤亡情况下有效(过量服药持续时间可达 24小时)。这项提议的总体目标是开发一种根本上新颖的药物输送方法，以扩大 目前FDA批准的阿片类过量解毒剂(纳洛酮和纳美芬)24小时或更长时间的DOA。这里 我们报道了新一代阿片拮抗剂前药的发展，作为合成的对策 阿片类药物过量。我们系统的主要优点包括：(I)使用FDA批准的两个 解毒剂，纳洛酮和纳美芬，具有良好的安全性和有效性；(2)逆转的可能性 并有效防止因合成阿片类药物过量而再次麻醉；(3)有可能避免 阿片类药物戒断症状的缓解；以及(Iv)皮下给药的能力。主 这一建议的假设是测试FDA批准的阿片拮抗剂的结合是否通过 可切割的酯连接到血清蛋白的选择性配体转甲状腺蛋白(Ttr)，将允许我们产生 阿片拮抗剂前药是亲水性的，可以可逆地与血清中的Ttr结合。平衡的 前药的亲水性对于实现皮下快速吸收前药具有重要意义。 组织与TTR结合时会延长前药的DOA。

Opioids have significant adverse effects highlighted by the large number of patients with opioid use disorder (OUD) and the increasing number of overdose deaths in the United States and elsewhere. In just the 12-month period ending in November 2021, more than 107,000 Americans died from drug overdose. Around 66% of these deaths involved illicit synthetic opioids like fentanyl (approximately 50 times more potent than heroin and 100 times more potent than morphine), which is the primary driver of the opioid epidemic today. Many of the opioid overdose deaths are attributed to fentanyl mixed with other illicit drugs like heroin, cocaine, and methamphetamine. The potential lethal dose of fentanyl is around two milligrams, and it is particularly dangerous for opioid naïve people who do not have a tolerance to opioids. Overdose deaths among high school-aged Americans have more than doubled since 2019, which has been attributed to counterfeit pills (e.g., Xanax, Percocet, Adderall) laced with a lethal amount of fentanyl. Sadly, many users often ingest the deadly drug unknowingly. Unfortunately, there is not a happy ending for this devastating story and there is no easy solution to the synthetic opioid problem. The vulnerability of our nation to the weaponization of highly potent fentanyl analogs, such as carfentanil (20-fold more potent than fentanyl), poses a significant public health risk not only to civilians, but also to first responders, law enforcement personnel, and the military. The relatively short duration of action (DOA) of the mu-opioid receptor antagonists, naloxone and nalmefene, poses a major challenge for its efficacy against fentanyl overdose. It is difficult to imagine how naloxone and nalmefene could be deployed effectively in a mass casualty situation involving synthetic opioids (where duration of overdose could last up to 24 hr). The overall goal of this proposal is to develop a fundamentally novel drug delivery approach for extending the DOA of currently FDA-approved opioid overdose antidotes (naloxone and nalmefene) for 24 hr or more. Here we report the development of a new generation of opioid antagonist prodrugs as a countermeasure for synthetic opioid overdose. The main advantages of our system include the following: (i) use of two FDA-approved antidotes, naloxone and nalmefene, with well-established safety and efficacy profiles; (ii) potential to reverse AND effectively protect against re-narcotization by synthetic opioid overdose; (iii) potential to avoid the precipitation of opioid withdrawal symptoms; and (iv) ability to administer the prodrugs subcutaneously. The main hypothesis of this proposal is to test whether conjugation of FDA-approved opioid antagonists through a cleavable ester linker to a selective ligand for the serum protein, transthyretin (TTR), would allow us to generate opioid antagonist prodrugs that are hydrophilic and can bind reversibly to TTR in serum. The balanced hydrophilicity of prodrug will be important for achieving rapid absorption of the prodrug from the subcutaneous tissue while binding to TTR would extend the DOA of the prodrugs.