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

阿片类药物具有显著的不良反应，突出表现为大量阿片类药物使用障碍患者 (OUD)以及美国和其他地方过量死亡人数的增加。在短短的12个月内， 截至2021年11月，超过107，000名美国人死于药物过量。其中约66% 死亡涉及非法合成阿片类药物，如芬太尼（大约比海洛因强50倍，比海洛因强100倍）。 比吗啡强一倍），这是今天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如海洛因，可卡因混合， 冰毒芬太尼的潜在致死剂量在两毫克左右，特别危险 对阿片类药物没有耐受性的阿片类药物初治者。高中生中的过量死亡 自2019年以来，美国人增加了一倍多，这归因于假药（例如，阿普唑仑， Percocet，Adderall）与致命数量的芬太尼混合。可悲的是，许多使用者经常摄入致命的药物， 在不知不觉中不幸的是，这个毁灭性的故事没有一个快乐的结局，也没有简单的解决办法 合成阿片类药物的问题我们的国家对高效力芬太尼武器化的脆弱性 类似物，如卡芬太尼（比芬太尼强20倍），不仅对公众健康构成重大风险， 平民，也包括第一反应者，执法人员和军队。持续时间相对较短 μ-阿片受体拮抗剂纳洛酮和纳美芬的作用时间（DOA）对其治疗构成了重大挑战。 对芬太尼过量的有效性。很难想象纳洛酮和纳美芬是如何部署的 有效地在涉及合成阿片类药物的大规模伤亡情况下（其中过量的持续时间可能持续长达 24小时）。该提案的总体目标是开发一种从根本上新颖的药物递送方法， 目前FDA批准的阿片类药物过量解毒剂（纳洛酮和纳美芬）的DOA为24小时或更长时间。这里 我们报道了新一代阿片拮抗剂前药的开发，作为合成阿片类药物的对策。 阿片类药物过量我们的系统的主要优点包括：（i）使用两个FDA批准的 解毒剂，纳洛酮和纳美芬，具有良好的安全性和疗效特征;（ii）逆转 并有效防止合成阿片类药物过量导致的再麻醉;（iii）避免 阿片样物质戒断症状的沉淀;和（iv）皮下施用前药的能力。主要 该建议的假设是测试FDA批准的阿片类拮抗剂是否通过 与血清蛋白的选择性配体甲状腺素运载蛋白（TTR）连接的可裂解酯接头将使我们能够产生 阿片样物质拮抗剂前药是亲水性的，并且可以可逆地结合血清中的TTR。均衡 前药的亲水性对于实现前药从皮下快速吸收是重要的 组织，同时结合TTR将延长前药的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.