Nanoparticle Generator for Animal Inhalation Experiments

描述(申请人提供)：该项目计划开发一种通用交钥匙药物纳米颗粒发生器(DNG)。这种粒子发生器的一个直接应用是在动物模型中测试新的可吸入药物。大多数吸入疗法的动物模型，如小鼠和仓鼠，都比人类小得多，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，沉积效率一直提高到几十nm。本装置在这种大小范围内工作，非常适合于将药物输送到动物模型的深肺。DNG产生高浓度的细小颗粒(&gt；107颗粒/毫升)，因此很容易在动物的肺部沉积微克量的药物。这将使对一些吸入疗法的候选药物进行有意义的疗效和安全性研究成为可能。 在第一阶段项目中，我们论证了基于高频超声雾化药物溶液然后扩散干燥的DNG概念的可行性。建造了一个原型，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将足够量的化学预防药二氟甲基鸟氨酸(DFMO)输送到A/J小鼠的可行性。第二阶段项目的目标是建立一个交钥匙版本的DNG，将以可靠和可重复的方式输送药物颗粒。该装置计划用于研究吸入性药物(DFMO和多西紫杉醇)在A/J小鼠体内的生物分布随颗粒大小的变化。多西紫杉醇将被研究，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将用于将放射性颗粒输送到A/J小鼠，以确定药物对肺周围区域的渗透程度与颗粒大小的关系。 DNG技术还有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。 该项目与吸入疗法治疗深部肺癌(腺癌)有直接关系。它提供了一种药物纳米颗粒发生器，对于使用小动物进行吸入性研究是必不可少的。该项目计划包括与吸入给药有关的化学预防和化疗药物的沉积和生物分布研究，随后将在未来的一个项目中进行安全性和有效性研究，并将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.