Evaluation of Liposomal Nicotine Vaccines for Repeated Pulmonary Administration

项目摘要 免疫药物治疗，也称为成瘾疫苗，代表了一种新兴的治疗策略， 尼古丁依赖的治疗这些成瘾疫苗诱导抗体的产生， 尼古丁分子，并将其隔离在外围，以减轻其奖励作用。而 已经对尼古丁疫苗进行了几项II期和III期临床试验，没有一项研究 可注射制剂导致所有患者的戒烟率提高。然而，在这方面， 对数据的进一步检查显示出乐观的理由。虽然没有一种测试的疫苗诱导 在所有接受治疗的受试者中，那些能够获得最强免疫应答的患者， 发现免疫应答具有更高的成功戒烟的机会。 这些观察结果表明，虽然使用尼古丁疫苗背后的原则是有效的，但改善了 需要管理策略来提高尼古丁疫苗接种的总体功效和剂量灵活性 战略布局因此，我们的目标是产生适合于肺部施用的尼古丁疫苗，其使用 脂质体缀合的半抗原。有了这个配方，这种肺部尼古丁疫苗的能力， 将测量产生可溶性IgA偏向的免疫应答和减少尼古丁向大脑的递送。 接下来，将使用慢性间歇性暴露于尼古丁蒸汽引起的尼古丁依赖模型 为了测量这种脂质体疫苗减轻症状和消除由于尼古丁引起的厌恶的能力， 戒断最后，将评估脂质体颗粒在小鼠肺中的解剖分布， 使用放射性标记的示踪剂雾化后体内。 总之，假设脂质体疫苗的肺部施用将导致强烈的免疫应答。 和行为反应，并且该制剂将适合于气雾剂施用。成功 这些特征的证明将提供尼古丁的肺部递送 疫苗可以通过重复的气雾剂自我- 局如果与雾化尼古丁一起提供，这种疫苗给药机制可以 甚至有可能通过持续使用尼古丁的生物反馈而自然产生。这将代表 这是该领域的一个重大突破，消除了个体间的差异，这是实现这一目标的障碍 戒烟的全民有效性。

PROJECT SUMMARY Immunopharmacotherapeutics, also called addiction vaccines, represent an emerging treatment strategy for the treatment of nicotine dependence. These addiction vaccines induce the production of antibodies that bind to nicotine molecules and sequester them in the periphery in order to mitigate their rewarding effects. While several phase II and III clinical trials have been conducted with nicotine vaccines, none of the studied injectable preparations have resulted in improved rates of smoking cessation across all patients. However, further inspection of the data has presented cause for optimism. While none of the tested vaccines induced a robust immune response in all treated subjects, those patients who were able to mount the most robust immune responses were found to have a higher chance of successfully quitting. These observations indicate that while the principles behind the use of nicotine vaccines are valid, improved administration tactics are needed to improve the overall efficacy and dosing flexibility of nicotine vaccination strategies. Thus, we aim to generate a nicotine vaccine that is suitable for pulmonary administration using liposome-conjugated haptens. With this formulation in hand, the ability of this pulmonary nicotine vaccine to generate a soluble IgA-biased immune response and decrease nicotine delivery to the brain will be measured. Next, a model of nicotine dependence arising from chronic intermittent exposure to nicotine vapor will be used to measure the ability of this liposomal vaccine to diminish symptoms and place aversion due to nicotine withdrawal. Finally, the anatomical distribution of the liposomal particles in mouse lungs will be assessed ex vivo following aerosolization using a radiolabelled tracer. Overall, it is hypothesized that pulmonary administration of a liposomal vaccine will lead to vigorous immune and behavioural responses, and that this formulation will be suitable for aerosol administration. Successful demonstration of these characteristics would provide a proof-of-principle that pulmonary delivery of nicotine vaccines could enable the application of individualized dosing regimens via repeated aerosol self- administration. If provided alongside nebulized nicotine, such a mechanism of vaccine dosing could potentially even arise naturally, using biofeedback from continued nicotine use. This would represent a significant breakthrough for the field by removing inter-individual variability as an obstacle to the achievement of population-wide efficacy for smoking cessation.