Nicotine delivery to rodents with lung alveolar region-targeted aerosol tech

描述（由申请人提供）：本申请是对NIH/PSH 2010-2在NIDA 2下的“SBIR/STTR资助申请综合征集”，“药物滥用研究的替代给药剂型的开发”的回应。通过烟草的使用，尼古丁是使用最频繁的成瘾性药物之一，也是美国疾病、残疾和死亡的主要可预防原因。为了了解尼古丁对大脑和身体的众多影响，为了开发更有效、更安全的戒烟药物和治疗烟草相关疾病，需要尼古丁依赖动物模型。目前可用于体内动物模型的尼古丁应用方法有许多局限性。尼古丁不能到达肺部的气体交换区（肺泡）；因此，动脉尼古丁水平上升的时间过程和幅度无法与人类吸烟时的水平相比。这项拨款的目标是开发一种非侵入性的方法和工具，用于向啮齿动物模型输送尼古丁，以确保尼古丁进入血液循环和大脑的量足够和可控，与吸烟的人进入身体的速度相同。目的1。开发一种新的啮齿动物尼古丁传递方法并进行动物实验验证。我们将通过确定空气中的中位致死浓度（LC50）和中位有效浓度（EC50）来证明尼古丁递送的有效性，以诱导包括癫痫发作在内的神经行为改变。我们将优化尼古丁传递的参数，以确保啮齿动物血液中尼古丁浓度的时间过程与人类吸烟时血液中尼古丁的药代动力学特征相似。目标2。用所开发的方法设计和制造啮齿动物的尼古丁传递系统。暴露系统将提供两种选择：一种是用于精确和急性尼古丁研究的约束暴露系统，另一种是用于慢性研究的家庭笼内自由移动暴露系统。这些系统将被整合到我们公司开发的SmartCageTM平台中，该平台可以自动定量地监测尼古丁暴露期间啮齿动物的行为，这是成瘾研究的有力工具。这个第一阶段项目将开发一种非侵入性和有效的方法来给啮齿动物施用尼古丁，从而创建与人类吸烟中尼古丁血液浓度的时间过程和强度非常相似的动物模型。我们将为研究吸烟对尼古丁的急性影响和使用家庭笼的慢性影响提供一个重要的工具。该方法将对烟草相关疾病和尼古丁成瘾研究领域产生重大影响。本研究将对尼古丁替代疗法（NRT）戒烟具有重要意义。这个第一阶段的项目将为第二阶段的项目奠定基础，该项目将为大鼠和小鼠开发一系列商业产品，并有可能用于大麻、可卡因、海洛因等其他滥用药物。

DESCRIPTION (provided by applicant): This application is in response to NIH/PSH 2010-2 'Omnibus solicitation for SBIR/STTR Grant Application' under NIDA 2, "Development of Alternate Drug Delivery Dosage Forms for Drugs Abuse Studies". Through the use of tobacco, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. To understand the numerous effects of nicotine on the brain and body, and to develop more effective and safer medications for smoking cessation and for treatment of tobacco- related diseases, nicotine dependent animal models are required. Currently available nicotine application methods for in vivo animal models have a number of limitations. Nicotine fails to reach the gas-exchange region in the lungs (the alveoli); therefore, the time course and magnitude of the rise in arterial nicotine levels are not comparable to those of humans when smoking cigarettes. The goal of this grant is to develop a non-invasive method and toolkit for delivering nicotine to rodent models that ensure an adequate and controllable amount entering circulation and the brain at the same rate nicotine enters the bodies of humans smoking cigarettes. Aim 1. To develop a novel nicotine delivery method for rodents and to validate it with animal testing. We will demonstrate the effectiveness of nicotine delivery by determining median lethal concentration (LC50) in air and median effective concentration (EC50) for the induction of neurobehavioral changes including seizures. We will optimize the parameters of nicotine delivery to ensure the time course of blood nicotine concentrations in rodents resembles the pharmacokinetic profile in human blood when smoking cigarettes. Aim 2. Design and engineer the nicotine delivery systems for rodents with the method developed. The exposure systems will provide two options: a restraint exposure system for accurate and acute nicotine studies, and free-moving exposure systems inside home cages for chronic studies. These systems will be incorporated into the SmartCageTM platform developed by our Company that can automatically and quantitatively monitor rodent behavior during nicotine exposure, a powerful tool for addiction studies. This Phase I project will develop a noninvasive and effective method to administer nicotine to rodents, thereby creating animal models that closely resemble the time course and magnitude of nicotine blood concentrations in humans smoking cigarettes. We will provide an important tool for studying the acute nicotine effects of smoking cigarettes and chronic effects using home cages. This method will have a significant impact on the field of tobacco-related disease and nicotine addiction research. This study will have important implications in nicotine replacement therapy (NRT) for smoking cessation. This Phase I project will lay the groundwork for a Phase II project developing a commercial product series for rats and mice, with a potential for other drugs of abuse such as marijuana, cocaine, heroin and beyond. PUBLIC HEALTH RELEVANCE: As a result of tobacco usage, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. The goal of the proposed project is to develop a toolkit to administer nicotine to rodents. Such a toolkit will ensure control over the amount of nicotine entering circulation and the brain, allowing for the design of experiments in which the effects of nicotine in humans may be more accurately modeled. This method will provide a powerful tool for animal research to understand the numerous effects of nicotine on the brain and body. Furthermore, this method will serve as a platform to develop more effective and safer medications for smoking cessation and treatment of tobacco-related diseases.