Nanoparticle Generator for Animal Inhalation Experiments

描述（由申请人提供）：本项目计划开发通用交钥匙药物纳米颗粒发生器（DNG）。这种粒子发生器的直接应用是在动物模型中测试新的可吸入药物。大多数用于吸入疗法的动物模型，如小鼠和仓鼠，比人类小得多，它们的呼吸道也很小。它们的可吸入颗粒尺寸范围小于500 nm，沉积效率持续增加，低至几十nm。本装置在该尺寸范围内操作，并且理想地适合于将药物递送到动物模型的深肺。DNG产生高浓度（>107个颗粒/ml）的细颗粒，因此很容易将微克量的药物存款在动物的肺中。这将使有意义的疗效和安全性研究与吸入治疗的候选药物的数量。 在I期项目中，我们证明了基于药物溶液的高频超声雾化然后扩散干燥的DNG概念的可行性。制造了一个原型并进行了广泛的测试。它被用于初步的动物暴露实验，首次证明了通过吸入向A/J小鼠提供足够数量的化学预防剂二氟甲基鸟氨酸（DFMO）的可行性。第二阶段项目旨在构建DNG的交钥匙版本，该版本将以可重复的方式可靠地递送药物颗粒。该装置计划用于研究吸入药物（DFMO和多西他赛）在A/J小鼠中的生物分布（作为粒径的函数）。将对多西他赛进行研究，因为它是一种化疗药物，是腺癌吸入治疗的候选药物。此外，DNG将用于向A/J小鼠递送放射性颗粒，以确定药物渗透到肺的外周区域中作为颗粒尺寸的函数。 DNG技术也有希望通过呼吸机将细雾输送到人的肺部，并产生用于医疗应用的细干粉。 该项目与使用吸入疗法治疗深肺癌症（腺癌）直接相关。它提供了一种药物纳米颗粒发生器，这对使用小动物的吸入研究至关重要。该项目计划包括与化学预防和化学治疗药物的吸入给药有关的沉积和生物分布研究，随后将在未来的项目中进行安全性和有效性研究，并为这些可吸入药物的临床试验铺平道路。

DESCRIPTION (provided by applicant): A general-purpose turnkey drug nanoparticle generator (DNG) is planned to be developed in this project. An immediate application of such a particle generator is to test new inhalable drugs in animal models. Most animal models for inhalation therapy, like mice and hamsters, are much smaller than humans and their respiratory tracts are also small. Their respirable particle size range is less than 500 nm with deposition efficiency increasing consistently down to a few tens of nm. The present device operates in this size range and is ideally suited for delivery of drugs to the deep lung of animal models. DNG generates a high concentration (>107 particles/ml) of fine particles, so it is easy to deposit drugs in microgram quantities in animals' lungs. This would enable meaningful efficacy and safety studies with a number of candidate drugs for inhalation therapy. In Phase I project, we demonstrated the feasibility of DNG concept based on high-frequency ultrasonic nebulization of drug solutions followed by diffusion drying. A prototype was built and extensively tested. It was used for preliminary animal exposure experiments that demonstrated for the first time the feasibility of delivering a chemopreventive agent difluoromethylornithine (DFMO) to A/J mice in adequate quantities by inhalation. Phase II project is aimed at building a turnkey version of DNG that would deliver drug particles reliably and in a repeatable manner. This device is planned to be used for studies on biodistribution of inhaled drugs (DFMO and docetaxel) in A/J mice as a function of particle size. Docetaxel will be studied because it is a chemotherapeutic agent that is a candidate for inhalation therapy of adenocarcinoma. Further, DNG will be used for delivering radioactive particles to A/J mice, in order to determine the penetration of the drug into the peripheral regions of the lung as a function of particle size. The DNG technology is also promising for delivery of fine mist to human lungs through a ventilator and for generation of fine dry powder for medical applications. This project is directly relevant to the treatment of the cancer of deep lung (adenocarcinoma) using inhalation therapy. It provides a drug nanoparticle generator that is essential to inhalation studies using small animals. The project plan includes deposition and biodistribution studies relevant to inhalation delivery of a chemopreventive and a chemotherapeutic drug, which would be followed by safety and efficacy studies in a future project and would pave the way to clinical trials for these inhalable drugs.