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: 9255203
• 负责人: Cody James Wenthur
• 金额: $ 5.67万
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255203
• 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; Breathing; Characteristics; Chronic; Clinical Trials; Cryoultramicrotomy; Data; Deposition; Distal; Dose; Drug Kinetics; Electronic cigarette; Evaluation; Exhibits; Exposure to; Feedback; Formulation; Generations; Hand; Haptens; Human; Immune response; Immune system; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Individual; Injectable; Injection of therapeutic agent; Liposomes; Logic; Lung; Measures; Methods; Modeling; Mucous Membrane; Mus; Nebulizer; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Patients; Penetration; Pharmaceutical Preparations; Phase; 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; liposomal delivery; man; nicotine replacement; optimism; particle; response; smoking cessation; subcutaneous; treatment strategy; uptake; vaccination strategy; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vaping; vapor; 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.

项目总结 免疫药物疗法，也被称为成瘾疫苗，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，并将它们隔离在外围，以减轻它们的奖励作用。而当 已经用尼古丁疫苗进行了几项第二阶段和第三阶段的临床试验，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给出了乐观的理由。虽然测试的疫苗中没有一种会导致 在所有接受治疗的受试者中，那些能够获得最强健免疫反应的患者 研究发现，免疫反应成功戒烟的几率更高。 这些观察表明，虽然尼古丁疫苗使用背后的原则是有效的，但改进后的 要提高尼古丁疫苗的整体效果和剂量灵活性，需要采取管理策略 战略。因此，我们的目标是生产一种适用于肺部给药的尼古丁疫苗，使用 脂质体标记的半抗原。有了这个配方，这种肺尼古丁疫苗能够 将测量产生以IgA为导向的可溶性免疫反应和减少尼古丁向大脑的输送。 接下来，我们将使用一个长期间歇性接触尼古丁蒸气造成的尼古丁依赖模型。 为了测量这种脂质体疫苗减轻尼古丁引起的症状和反胃的能力 戒烟。最后，将评估脂质体颗粒在小鼠肺内的解剖分布。 使用放射性标记示踪剂雾化后的活体。 总体而言，假设肺部注射脂质体疫苗将导致强大的免疫力。 该配方适用于气雾剂的给药。成功 这些特征的证明将提供一个原则证明，尼古丁的肺部递送 疫苗可以通过反复喷雾自我接种来实现个性化给药方案的应用。 行政管理。如果与雾化尼古丁一起提供，这样的疫苗剂量机制可能 甚至可能是自然产生的，使用持续使用尼古丁的生物反馈。这将代表一个 该领域的重大突破，消除了个人间的差异，成为实现这一目标的障碍 在整个人群中戒烟的有效性。