Novel nanovaccines against opioid use disorders

项目摘要 阿片类药物使用障碍（OUD）是一种全国性的突发公共卫生事件，发生了115起以上的致命过量事件。 每天在美国。每年，OUD的经济负担超过780亿美元。有几种药物是 但是它们的可及性是有限的，并且功效通常是次优的。因此，迫切需要发展 新的和负担得起的策略来治疗OUD。免疫药物疗法已成为一种有前途的治疗方法 针对OUD。与涉及药理学激动剂的传统药物疗法相比， 作为阿片受体的拮抗剂，免疫药物疗法依赖于药物特异性抗体来结合阿片受体。 循环药物分子，以减少它们在大脑中的分布，从而减少阿片类药物诱导的行为 和毒性。接种疫苗可能是更安全和更具成本效益的免疫药物干预， 由于疫苗能够在患者中引发先天性和适应性免疫应答， 保护OUD。由于其选择性，预计疫苗不会干扰内源性阿片类药物 也不与用于疼痛管理或治疗OUD的阿片类药物一起使用。此外，可以将联合收割机疫苗 与目前的药物更有效的治疗OUD，因为不同的作用机制。电流 抗阿片类疫苗候选物主要是缀合物疫苗（阿片类半抗原-载体蛋白缀合物） 在免疫识别的佐剂中传递。虽然这些结合疫苗已经显示出有希望的预- 针对OUD的临床有效性和选择性，测试新的免疫平台是至关重要的， 提高了针对OUD疫苗效力。因此，本项目的目标是制造新型纳米颗粒基 针对OUD的疫苗，这可能会导致对目标阿片类药物的有效免疫反应， 这些独特的特征：1）有效呈递B细胞和T细胞表位，2）提高疫苗的摄取 颗粒，以及3）掺入分子佐剂以促进免疫细胞的协同活化。 适应性免疫途径该项目的创新之处在于将张博士独特的结构脂质- 聚合物纳米载体与Pravetoni博士完善的阿片类药物半抗原系列和临床前平台 来鉴定候选疫苗。开发将在UG 3/UH 3阶段交错进行，我们预计， 确定纳米疫苗的主要配方，提供对羟考酮，芬太尼或两者的保护， 一次该项目的广泛影响在于合理设计安全的纳米颗粒疫苗 对阿片类药物有效。这种新的基于纳米颗粒的免疫策略可以应用于 开发针对一系列OUD和其他物质使用障碍的下一代疫苗。

Project Summary Opioid use disorders (OUD) are a national public health emergency with more than 115 fatal overdoses occurring each day in the USA. Annually, the economic burden of OUD is over US$78 billion. Several medications are available for treating OUD, but their access is limited and efficacy is often sub-optimal. It is thus urgent to develop new and affordable strategies to treat OUD. Immunopharmacotherapy has emerged as a promising treatment approach against OUD. In contrast to traditional pharmacotherapies involving pharmacological agonists and antagonists of the opioid receptors, immunopharmacotherapy relies on drug specific antibodies to bind the circulating drug molecules to reduce their distribution to the brain, and thus reducing opioid-induced behaviors and toxicity. Vaccination is likely the safer and more cost-effective immunopharmacotherapeutic intervention, due to the ability of vaccines to trigger innate and adaptive immune responses in patients to offer long lasting protection against OUD. Due to their selectivity, vaccines are not expected to interfere with endogenous opioids nor with opioids used in pain management or treatment of OUD. Furthermore, it is possible to combine vaccines with current medications for more effective OUD treatment because of the different mechanism of action. Current anti-opioid vaccine candidates are primarily conjugate vaccines (opioid hapten-carrier protein conjugates) delivered in adjuvants for immune recognition. Although these conjugate vaccines have shown promising pre- clinical efficacy and selectivity against OUD, it is critical to test novel immunization platforms that may further improve vaccine efficacy against OUD. Hence, the goal of this project is to fabricate novel nanoparticle-based vaccines against OUD, which will likely lead to an effective immune response against the target opioid by offering these unique features: 1) efficient presentation of B cell and T cell epitopes, 2) improved uptake of vaccine particles by immune cells, and 3) incorporation of molecular adjuvants to promote a synergistic activation of adaptive immune pathways. The innovation of this project involves merging Dr. Zhang's uniquely structured lipid- polymer nanocarriers with Dr. Pravetoni's well-established opioid-based hapten series and pre-clinical platform to identify vaccine candidates. Development will be staggered across UG3/UH3 phases, and we expect to identify lead formulations of nanovaccines that offer protection against either oxycodone, fentanyl, or both at once. The broad impact of this project resides in the rational design of nanoparticle-based vaccines that are safe and effective against opioids. This novel nanoparticle-based immunization strategy can be applied to the development of next-generation vaccines against a range of OUD and other substance use disorders.