Inhalable Gallium Nitrate Anti-Infective Powder for CF

描述（申请人提供）：囊性纤维化（CF）是一种常染色体隐性遗传病，导致CF患者气道分泌物组成和物理性质异常。此外，CF患者的肺部特别容易受到慢性细菌感染，80%的CF患者在18岁时慢性感染铜绿假单胞菌的粘液样形式，过量产生表面多糖海藻酸盐。该项目的长期目标（超出本申请范围）是研究硝酸镓作为抗感染药物治疗慢性铜绿假单胞菌肺部感染的CF患者。需要验证的主要假设是硝酸镓是否可以减少铜绿假单胞菌肺部感染并改善肺功能。对CF中铜绿假单胞菌感染的一个关键观察是，尽管服用了一团抗生素，但患者最终还是死于细菌感染。据信，细菌耐药性是治疗失败的主要原因，使生物体逃脱获得性宿主免疫防御的消灭，是肺功能进行性下降的基础。在体外实验中发现，硝酸镓对革兰氏菌和革兰氏+菌都有杀菌作用，尤其是对慢性定植在CF患者肺部的细菌，如铜绿假单胞菌、洋葱伯克霍尔德菌和耐甲氧西林金黄色葡萄球菌（MRSA）。镓对从医院感染患者中分离的铜绿假单胞菌粘液株具有保护作用。初步数据表明，镓对细菌耐药菌株以及新近从新鲜痰中分离的菌株有效。为此，我们建议进一步开展硝酸镓的临床前开发，并测试其对野生型（WT）小鼠急性铜绿假单胞菌肺部感染的保护作用。我们将首先使用喷雾干燥工艺开发最佳气溶胶配方，表征气溶胶特性，并确认铅配方可以有效地从传统的市售吸入器中输送。我们将在小鼠吸入模型中对优化的气雾剂配方进行临床前测试，以评估其停留时间和生物分布，然后在细菌攻击研究中确定最小保护剂量。公共卫生相关性：本申请中提出的研究旨在进一步开发新的抗感染候选物硝酸镓，以治疗慢性铜绿假单胞菌CF患者的肺部感染。目前，80-95%的CF患者最终因慢性铜绿假单胞菌感染和气道炎症而死于呼吸衰竭。

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is an autosomal recessive disorder, which leads to the abnormal composition and physical properties of airway secretions in CF patients. Additionally, the lungs of CF patients are particularly susceptible to chronic bacterial infections with >80% of CF patients becoming chronically infected by 18 years of life with mucoid forms of Pseudomonas aeruginosa that over-produce the surface polysaccharide alginate. The long term goal of this project (which is outside the scope of this application) is to investigate the use of gallium nitrate as an anti-infective to treat chronic P. aeruginosa lung infections in CF patients. The major hypothesis to be tested is whether gallium nitrate can be used to reduce P. aeruginosa lung infections and result in improvement in lung function. One key observation of P. aeruginosa infections in CF is that the patients ultimately succumb to bacterial infections despite being on a regiment of antibiotics. It is believed that bacterial resistance is a major reason for treatment failure, allowing the organism to escape elimination by acquired host immune defenses and underlies the progressive decline in lung function. Gallium nitrate was found to be bactericidal in vitro against both Gram- and Gram+ bacteria, particularly against bacteria that are found to chronically colonize the lungs of CF patients, such as P. aeruginosa, Burkholderia cepacia and methycillin-resistant Staphylococcus aureus (MRSA). Galllium was protective against mucoid strains of P. aeruginosa isolated from patients with nosocomial infections. Preliminary data indicate that gallium is effective against bacterial resistant Pa strains as well as recent strains isolated from fresh sputum. In this application, we propose further preclinical development of gallium nitrate and testing the protective activities against acute P. aeruginosa pulmonary infection in wild- type (WT) mice. We will first develop an optimal aerosol formulation using a spray drying process, characterize the aerosol properties, and confirm that lead formulations can be efficiently delivered from conventional, commercially available inhalers. We will perform preclinical testing of optimized aerosol formulation in a mouse inhalation model to assess its residence time and biodistribution, followed by determination of the minimal protective dose in a bacterial challenge study. PUBLIC HEALTH RELEVANCE: The studies proposed in this application are designed to further development of a new anti-infective candidate gallium nitrate to treat chronic Pseudomonas aeruginosa lung infections of CF patients. At present, 80-95% of CF patients ultimately succumb to respiratory failure due to chronic P. aeruginosa infection and airway inflammation.