Sustained Release Pulmonary Delivery for Improved Cystic Fibrosis Treatment

持续释放肺部给药以改善囊性纤维化治疗

• 批准号: 7478014
• 负责人: LINDA A. FELTON
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478014
• 关键词: Address; Adverse effects; Aerosols; Alveolar Macrophages; Biocompatible; Biological Models; Breathing; Bronchoalveolar Lavage Fluid; Caliber; Cell Culture System; Characteristics; Cystic Fibrosis; Data; Deposition; Development; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; End Point; Environment; Evaluation Studies; Feasibility Studies; Future; Goals; Hydrogels; In Vitro; Infection; Inflammation; Inflammatory; Investigation; Lead; Lung; Lung Inflammation; Metabolism; Modeling; Mucolytics; Mucous body substance; Outcome; Particle Size; Penetration; Performance; Pharmaceutical Preparations; Physiological; Plasma; Polyethylene Glycols; Polymers; Powder dose form; Property; Pulmonary Cystic Fibrosis; Quality of life; Range; Rate; Rattus; Relative (related person); Research; Safety; Site; Structure of parenchyma of lung; Swelling; System; Therapeutic; Therapeutic Agents; Time; Work; airway obstruction; biomaterial compatibility; compliance behavior; controlled release; cystic fibrosis airway; cystic fibrosis patients; design; desire; gene therapy; improved; in vivo; innovation; macrophage; novel; novel strategies; particle; size; uptake

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.

描述（由申请人提供）：过去 30 年来，囊性纤维化 (CF) 的治疗取得了重大进展。特别是，通过吸入气雾剂直接治疗肺部的药物可以改善结果并减少常见疗法的副作用。然而，由于气道阻塞、气道内粘稠粘液运输障碍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患者的吸入疗法的疗效显着降低。通常，在药物活性降低或消除之前，药物无法达到预期目标。效率差会导致给药时间延长和患者依从性降低。考虑到治疗障碍的研究水平，囊性纤维化治疗中缺乏药物输送创新令人惊讶。长期目标是克服这些障碍并实现 CF 治疗的重大改进。该研究的中心假设是，当以气雾剂形式给药时，新型功能化颗粒将促进模型治疗剂的持续释放，与通过囊性纤维化粘液屏障的扩散和渗透相关。我们的初步数据表明，（1）新型颗粒可以负载一系列治疗剂，（2）它们可以制备为可呼吸气雾剂，（3）使用这些颗粒可以显着增强粘液渗透性，（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方法的基本原理和可行性。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，该系统同时允许控制肺部沉积、避免肺部清除机制并增强 CF 疾病中的转运。这些系统将提供持续的高药物浓度，直接输送到作用部位，因此将有助于显着改善 CF 的药物和基因疗法，延长生存期并提高生活质量。因此，该项目的具体目标是（i）制备适合通过干粉雾化和靶向肺部沉积吸入的载药功能颗粒，（ii）在体外和与 CF 疾病相关的生物模型中表征用于 CF 治疗的颗粒的药物释放和递送性能，以及（iii）评估缓释肺部递送系统与立即释放气雾剂的体内功效。拟议工作的结果将用于设计气溶​​胶治疗 CF 肺部疾病的新方法。拟议的研究将填补我们对缓释肺部药物输送系统以及随后药物和基因疗法的控制给药如何影响 CF 治疗策略的理解的重要空白。这些 R03 可行性研究启动了将药物输送方法应用于 CF 治疗的长期目标。