Evaluation of Liposomal Nicotine Vaccines for Repeated Pulmonary Administration

脂质体尼古丁疫苗反复肺部给药的评价

• 批准号: 9471217
• 负责人: Cody James Wenthur
• 金额: $ 2.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2018-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9471217
• 关键词: Achievement; Acute; Aerosols; Alcohol or Other Drugs use; Anatomy; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Attention; Autoradiography; Binding; Biofeedback; Biological Assay; Blood; Brain; Characteristics; Chronic; Cryoultramicrotomy; Data; Deposition; Distal; Dose; Drug Kinetics; Electronic cigarette; Evaluation; Exhibits; Feedback; Formulation; Generations; Hand; Haptens; Human; Immune response; Immune system; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Injectable; Injections; Liposomes; Logic; Lung; Measures; Methods; Modeling; Mucous Membrane; Mus; Nebulizer; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Patients; Penetration; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Population; Preparation; Process; Production; Protocols documentation; Radiolabeled; Rattus; Regimen; Respiratory System; Rewards; Schedule; Self Administration; Site; Smoking; Structure of parenchyma of lung; Symptoms; System; Testing; Time; Tracer; Translations; Vaccines; Weaning; Withdrawal Symptom; absorption; addiction; behavioral outcome; behavioral response; flexibility; improved; individual variation; inter-individual variation; liposomal delivery; man; nicotine exposure; nicotine inhalation; nicotine replacement; nicotine use; nicotine vaccine; nicotine vapor; optimism; particle; response; smoking cessation; subcutaneous; treatment strategy; uptake; vaccination strategy; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vaping; virtual

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.

项目摘要 免疫药物治疗药，也称为成瘾疫苗，代表了新兴的治疗策略 尼古丁依赖性的治疗。这些成瘾疫苗诱导结合的抗体产生 为了减轻其奖励作用，将尼古丁分子隔离并隔离它们。尽管 已经使用尼古丁疫苗进行了几项II期和III期临床试验，没有研究 可注射的准备工作导致所有患者的戒烟发生率提高。然而， 对数据的进一步检查提出了乐观的原因。虽然没有测试的疫苗诱导 在所有治疗受试者中，强大的免疫反应，那些能够安装最强大的患者 发现免疫反应成功退出的机会更高。 这些观察结果表明，尽管使用尼古丁疫苗的原理是有效的，但改进了 需要进行管理策略来提高尼古丁疫苗接种的整体疗效和剂量灵活性 策略。因此，我们旨在生成适合使用肺部给药的尼古丁疫苗 脂质体结合的触觉。掌握了这种配方，这种肺尼古丁疫苗的能力 将测量产生可溶性IGA偏置的免疫反应，并减少向大脑的尼古丁递送。 接下来，将使用由慢性间歇性暴露于尼古丁蒸气引起的尼古丁依赖模型 测量这种脂质体疫苗减轻症状并因尼古丁引起的厌恶的能力 提取。最后，将评估小鼠肺中脂质体颗粒的解剖学分布 使用放射性标记的示踪剂使体内雾化后。 总体而言，假设肺动物疫苗的肺部给药将导致剧烈免疫 和行为反应，并且该配方适用于气溶胶给药。成功的 这些特征的演示将提供原则证明尼古丁的肺部递送 疫苗可以通过反复的气溶胶自我实现个性化给药方案的应用 行政。如果与雾化的尼古丁一起提供，则这种疫苗给药机制可能 使用持续使用尼古丁的生物反馈自然而然地出现。这将代表一个 通过消除个体间的可变性作为成就的障碍，对该领域的重大突破 范围内戒烟的疗效。