Novel Therapies for Enhancing Clearance of Inhaled Radioactive Particles

描述（由申请人提供）：在此申请中，我们提出了一个研究和开发项目，目标是通过产品开发过程推进放射性物质吸入暴露的治疗对策。正如下面所讨论的，受到放射性物质攻击（如脏弹）后对肺部的最大危险是吸入和保留不溶性放射性颗粒。由于放射性颗粒滞留，肺部累积暴露量显著增加，最终导致肺纤维化/肺炎和死亡。不溶性颗粒不能被螯合剂全身清除，因为它们不在溶液中。迄今为止，通过支气管肺泡灌洗物理去除颗粒物是唯一一种被证明能有效缓解辐射引起的肺部疾病的治疗方案。在这个应用中，我们将测试新化合物通过增强肺表面的水合作用来加速肺中不溶性颗粒的去除的能力。药理学诱导的肺表面水化增加增加了(1)气道表面颗粒的机械清除和(2)肺泡巨噬细胞清除的增加。从本质上讲，我们的化合物通过气溶胶途径对肺部产生“非侵入性灌洗”，可以与其他可用的治疗策略协同使用，作为减少累积辐射暴露的手段，从而减轻肺部疾病。我们的方法的优点是多方面的。首先，我们的策略不是同位素选择性的，它将有助于清除肺部的任何不溶性颗粒。重要的是，我们已经成功地完成了动物和人类的概念验证研究，证明我们的化合物通过将粘膜纤毛清除率（MCC）提高10倍以上，有效地促进放射性颗粒的清除。其次，我们的化合物有广泛的安全性和毒理学数据，这将促进这种治疗方法的快速可用性。我们的先导化合物552-02，已经进行了六次人体临床试验，没有出现任何严重的不良反应。此外，我们在552-02的大规模合成、稳定性、配方和递送方面取得了实质性进展。在这项应用中，我们建议测试我们的化合物作为单独治疗和与支气管肺泡灌洗的联合治疗，这是目前唯一显示有效去除肺部不溶性放射性核素的治疗方法。我们的目标是确定最有效的治疗对策，以防止吸入暴露后放射性诱发的肺部疾病。

DESCRIPTION (provided by applicant): In this application, we propose a research and development project with the goal of advancing a therapeutic countermeasure for radiological material inhalation exposure through the product development process. As discussed below, the greatest risk to the lungs following a radiological attack, such as a dirty bomb, results from the inhalation and retention of insoluble radioactive particles. As a result of radioactive particle retention, the cumulative exposure to the lung is significantly increased, ultimately resulting in pulmonary fibrosis/pneumonitis and death. Insoluble particles cannot be systemically cleared by chelating agents as they are not in solution. To date, the physical removal of particulate matter through bronchoalveolar lavage is the only therapeutic regimen shown to be effective at mitigating radiation-induced lung disease. In this application, we will test the ability of novel compounds to accelerate the removal of insoluble particles in the lung by enhancing hydration of pulmonary surfaces. Pharmacologically induced increases in pulmonary surface hydration increase both (1) mechanical clearance of particles from airway surfaces and (2) increases in alveolar macrophage clearance. In essence, our compounds via the aerosol route produce a 'non-invasive lavage' of the lung which can be used in concert with other available therapeutic strategies as a means to decrease the cumulative radiation exposure and therefore, mitigate lung disease. The advantages of our approach are several-fold. First, our strategy is not isotope selective and will facilitate clearance of any insoluble particles from the lungs. Importantly, we have successfully completed proof-of-concept studies in animals and humans which demonstrate that our compounds efficaciously facilitate radioactive particle clearance by increasing mucociliary clearance (MCC) greater than 10-fold. Second, we have extensive safety and toxicology data for our compounds that will promote rapid availability of this therapeutic. Our lead compound, 552-02, has been in six human clinical trials without any serious adverse events. Furthermore, we have made substantial progress towards 552-02 development with respect to large scale synthesis, stability, formulation, and delivery. In this application, we propose to test our compounds as both a stand alone therapy and in combination with bronchoalveolar lavage, the only treatment presently shown to effectively remove insoluble radionuclides from the lungs. Our goal is to identify the most effective therapeutic countermeasure against radiological-induced lung disease following inhalation exposure.