Sustained Release Pulmonary Delivery for Improved Cystic Fibrosis Treatment

描述（由申请人提供）：在过去的30年里，囊性纤维化（CF）的治疗有了显著的改善。特别是，通过吸入气雾剂直接治疗肺部的药物递送具有改善的结果和减少的常见疗法的副作用。然而，由于气道阻塞、气道内的粘性粘液转运屏障以及吸入药物在发挥其药理作用之前的广泛降解和代谢，CF患者中吸入治疗的功效显著降低。通常药物在其活性降低或消除之前不会到达预期目标。效率差导致给药时间延长和患者依从性降低。考虑到对治疗障碍的研究水平，缺乏应用于治疗囊性纤维化的疗法的药物递送创新是令人惊讶的。长期目标是克服这些障碍，实现CF治疗的关键改进。所提出的研究的中心假设是，当作为气雾剂施用时，新型功能化颗粒将促进模型治疗剂的持续释放，其与通过囊性纤维化粘液屏障的扩散和渗透相关。我们的初步数据已经证明，（1）新型颗粒可以装载有一系列治疗剂，（2）它们可以被制备为可吸入气雾剂，（3）使用这些颗粒可以实现显著增强的粘液渗透，以及（4）它们可以实现药物的持续释放，同时避免肺泡巨噬细胞清除。这些令人兴奋的初步数据，有力地支持了所提出的方法的合理性和可行性。拟议研究的主要目标是开发，合成，表征和评估新型颗粒载体系统，同时允许控制肺沉积，避免肺清除机制，并增强CF疾病的运输。这些系统将提供持续的高药物浓度，直接递送到作用部位，因此将促进CF中药物和基因治疗的显著改善，延长生存期并提高生活质量。因此，本项目的具体目标是（i）制备适于通过干粉雾化和靶向肺沉积吸入的载药功能颗粒，（ii）在体外和CF疾病相关生物模型中表征CF治疗用颗粒的药物释放和递送性能，以及（iii）评价缓释肺递送系统与速释气雾剂的体内疗效。拟议的工作的结果将被用来设计新的方法，用于CF肺病的气雾剂治疗。拟议的研究将填补我们对持续释放肺部药物递送系统的理解的重要空白，以及随后药物和基因治疗的控制给药如何影响CF治疗策略。这些R03可行性研究启动了将药物递送方法应用于CF治疗的长期目标。

DESCRIPTION (provided by applicant): Significant improvements in the treatment of cystic fibrosis (CF) have occurred over the past 30 years. In particular, drug delivery via inhalation aerosols to treat the lungs directly has improved outcomes and reduced side effects from common therapies. However, the efficacy inhaled therapies is dramatically reduced in CF patients because of airway obstruction, viscous mucus transport barrier within the airways, and extensive degradation and metabolism of inhaled drug prior to exerting its pharmacological action. Often drugs will not reach the intended target before their activity has been reduced or eliminated. Poor efficiencies lead to extended dosing times and decreased patient compliance. The lack of drug delivery innovation applied to therapies for the treatment of cystic fibrosis is surprising given the level of investigation of the barriers to treatment. The long term objectives are to overcome these barriers and achieve critical improvements in CF therapy. The CENTRAL HYPOTHESIS of the proposed research is that novel functionalized particles will facilitate sustained release of model therapeutic agents with relevance to diffusion and penetration through cystic fibrosis mucus barriers when administered as an aerosol. Our preliminary data have demonstrated that (1) the novel particles can be loaded with a range of therapeutics, (2) they can be prepared as respirable aerosols, (3) significantly enhanced mucus permeation can be achieved using these particles and (4) they can achieve sustained release of drug while avoiding alveolar macrophage clearance. These exciting preliminary data, strongly support the rationale and feasibility of the proposed approach. The main objective of the proposed research is to develop, synthesize, characterize, and evaluate novel particle carrier systems that simultaneously allow controlled lung deposition, avoidance of lung clearance mechanisms, and enhanced transport in CF disease. These systems will provide sustained high drug concentrations delivered directly to the site of action and will therefore facilitate significant improvements in drug and gene therapies in CF, prolonging survival and enhancing quality of life. Therefore, the SPECIFIC AIMS of this project is to (i) Prepare drug loaded functional particles suitable for inhalation via a dry powder aerosolization and targeted lung deposition, (ii) Characterize Drug Release and Delivery Performance of Particles for CF Therapy in vitro and in biological models relevant to CF disease, and (iii) Evaluate in vivo efficacy of sustained release pulmonary delivery system versus immediate release aerosols. The results of the proposed work will be used to design novel approaches for the aerosol treatment of CF lung disease. The proposed studies will fill important gaps in our understanding of the systems of sustained release pulmonary drug delivery and subsequently how controlled administration of drug and gene therapies may impact CF treatment strategies. These R03 feasibility studies, initiate a long term goal of applying drug delivery approaches to CF therapy.