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.

项目概要 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。这些成瘾疫苗诱导产生结合的抗体 尼古丁分子并将其隔离在外围，以减轻其奖励效应。尽管 尼古丁疫苗已经进行了多项 II 期和 III 期临床试验，但没有一项研究 注射制剂提高了所有患者的戒烟率。然而， 对数据的进一步检查显示出乐观的理由。虽然所测试的疫苗均未诱发 所有接受治疗的受试者都产生了强大的免疫反应，这些患者能够产生最强大的免疫反应 研究发现免疫反应有更高的成功戒烟机会。 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，但改进的 需要采取管理策略来提高尼古丁疫苗接种的整体功效和剂量灵活性 策略。因此，我们的目标是生产一种适合肺部给药的尼古丁疫苗 脂质体缀合的半抗原。有了这种配方，这种肺尼古丁疫苗就能 产生可溶性 IgA 偏向免疫反应并减少尼古丁向大脑的输送将被测量。 接下来，将使用因长期间歇性接触尼古丁蒸气而产生的尼古丁依赖模型 测量这种脂质体疫苗减轻症状和消除尼古丁厌恶的能力 撤回。最后，将评估脂质体颗粒在小鼠肺部的解剖分布 使用放射性标记示踪剂雾化后体内。 总体而言，假设脂质体疫苗的肺部给药将导致强烈的免疫 和行为反应，并且该制剂适合气雾剂给药。成功的 这些特性的证明将为尼古丁的肺部输送提供原理证明 疫苗可以通过重复气雾剂自我调节来应用个体化给药方案 行政。如果与雾化尼古丁一起提供，这种疫苗剂量机制可以 甚至可能通过持续使用尼古丁的生物反馈自然产生。这将代表一个 通过消除个体间差异作为成就的障碍，在该领域取得重大突破 整个人群的戒烟功效。