Surface Active Polyelectrolyte Nanomedicine for Treatment of Lung Infections in Cystic Fibrosis

项目总结/摘要 囊性纤维化（CF）是一种遗传性疾病，由囊性纤维化基因突变引起。 纤维化跨膜传导调节因子（CFTR）基因。预期寿命只有42岁，85%的人 肺部疾病并发症导致的死亡率。由于肺中粘液的积聚， CF的标志，患者遭受各种革兰氏阳性和革兰氏阴性的慢性细菌感染 种，最值得注意的是铜绿假单胞菌和金黄色葡萄球菌。这些问题更加复杂， CF痰液中细菌生物膜的形成以及多重耐药微生物的出现 （MDRO）菌株（QED 1）。需要非常高的抗生素剂量来根除生物膜感染， 会导致严重的副作用 目前对患有铜绿假单胞菌感染的CF患者的护理标准是用以下药物治疗： 氨基糖苷类、妥布霉素，通过雾化器或干粉吸入器吸入给药。一些CF 中心采用粘菌素，这是一种阳离子抗菌肽（CAP），作为第二线抗生素治疗; 然而，在美国还没有批准的粘菌素吸入形式，而全身给药 由于肾毒性的风险，建议使用。目前还没有批准的药物输送技术， 同时需要肺特异性递送和穿透富含 粘液并被慢性细菌生物膜定殖。 我们的实验室已经开发出具有“智能”表面活性化学的接枝聚电解质， 促进与带电生物分子货物的自组装和穿过限制生物分子的生理屏障， 毒品分销我们假设这些表面活性聚电解质可以被调整以自组装， CAP和氨基糖苷类两者以形成纳米颗粒，所述纳米颗粒随后可以使用喷雾器雾化。 此外，我们假设这些雾化的纳米颗粒将提供改善的渗透到 粘液水凝胶样环境的CF患者的肺，使控制释放，并发挥改善 抗铜绿假单胞菌和CF患者常见的其他菌株的生物膜的活性。为了测试这些 假设，并为这种方法提供概念证明，这种方法易于翻译， 改变CF患者的游戏规则，我们将：（1）开发载有妥布霉素的纳米颗粒， 粘菌素（单独和组合），并研究其控释行为;评估其能力， - 表面活性纳米颗粒穿透粘液和生物膜屏障的能力及其抗微生物活性;以及 (3)评价给药后小鼠对载体和药物有效载荷的局部和全身暴露 全身或通过喷雾器吸入。

PROJECT SUMMARY/ABSTRACT There is no cure for cystic fibrosis (CF), which is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) genes. Life expectancy is only 42 years, with 85% of the mortality due to complications from lung disease. Owing to the buildup of mucus in the lungs, which is a hallmark of CF, patients suffer chronic bacterial infections of a variety of Gram-positive and Gram-negative species, most notably Pseudomonas aeruginosa and Staphylococcus aureus. These are complicated further by the formation of bacterial biofilms within CF sputum and by the emergence of multi-drug resistant organism (MDRO) strains (QED1). Very high antibiotic dosages are needed for eradication of biofilm infections, which can lead to serious adverse side effects. The current standard of care for CF patients with P. aeruginosa infections is treatment with the aminoglycoside, tobramycin, administered via inhalation with a nebulizer or dry powder inhaler. Some CF centers employ colistin, which is a cationic antimicrobial peptide (CAP), as a second line of antibiotic therapy; however, there is not an approved inhalation form of colistin in the U.S., and systemic administration is not recommended due to the risk of nephrotoxicity. There is no approved drug delivery technology that addresses the simultaneous need for lung-specific delivery and the challenge of penetrating a lung environment rich with mucus and colonized with chronic bacterial biofilms. Our laboratory has developed graft polyelectrolytes with “smart,” surface-active chemistry that facilitates self-assembly with charged biomolecular cargoes and passage across physiological barriers that limit drug distribution. We hypothesize that these surface-active polyelectrolytes can be tuned to self-assemble with both CAPs and aminoglycosides to form nanoparticles that can subsequently be aerosolized using a nebulizer. Furthermore, we hypothesize that these aerosolized nanoparticles will provide improved penetration into the mucus hydrogel-like environment of the lungs of CF patients, enable controlled release, and exert improved activity against biofilms of P. aeruginosa and other strains common to CF patients. In order to test these hypotheses and provide proof of concept for this approach, which is readily translatable and potentially a game-changer for CF patients, we will: (1) develop polyelectrolyte nanoparticles loaded with tobramycin and colistin (individually and in combination) and investigate their controlled release behavior; evaluate the ability of the surface-active nanoparticle to penetrate mucus and biofilm barriers and their antimicrobial activity; and (3) evaluate the regional and systemic exposure of mice to carrier and drug payload following administration either systemically or by nebulizer inhalation.