Theranostic Approach to Asthma Using Anti-Angiogenic Nanomedicine

描述(申请人提供)：哮喘是一种慢性炎症性肺部疾病，估计有2300万美国人(1600万成年人)受到影响，其中1200万人每年至少经历一次哮喘发作。哮喘的症状给医疗保健系统造成了巨大的经济负担(2008年为180亿美元)，并对患者的生活质量产生了重大影响。哮喘的特征是呼吸道炎症和浮肿。最近，长期以来公认的气道壁微血管密度的增加和血容量的扩大被认为对肺功能有显著贡献。该项目结合了伊丽莎白·瓦格纳教授(PI)和格雷戈里·M·兰扎教授(PD/PI)在肺血管生成生理学方面的公认专业知识，他的基于纳米医学的分子成像和治疗是众所周知的，特别是在癌症和动脉粥样硬化的血管生成方面。这项建议的主要假设是使用纳米医学方法来非侵入性地表征支气管血管生成(新血管形成)，提供急性抗血管生成治疗以减少气道重塑和改善肺功能，并维持这一新治疗的急性益处，使用标准护理的小剂量类固醇。 公共卫生相关性：哮喘的病理特征是呼吸道上皮损伤、嗜酸性粒细胞浸润、平滑肌增生和基底膜增厚所致的气道结构重建。长期以来，气道壁内血管数量和大小的增加一直被认为是哮喘重塑的一个因素，发生在青年和老年患者的轻度、中度和重度哮喘肺中。然而，最近的研究指出，慢性哮喘的严重程度与微血管密度增加之间存在功能关系，这表明微血管血容量对呼吸道阻塞有显著影响。这一建议的主要假设是，纳米医学方法可以有效地使用：1)非侵入性量化支气管血管生成，2)提供急性抗血管生成治疗以减少气道重塑和改善肺功能，以及3)维持小剂量类固醇抗血管生成治疗的急性益处。这种治疗哮喘的纳米医学方法将定量图像分层和有针对性的前药物纳米疗法与当前的护理药物标准相结合，提供了一种临床上可翻译的方法，以改善中度到重度哮喘的进展，最终减少住院和家庭保健成本。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory lung disease that affects an estimated 23 million Americans (16 million adults), 12 million of whom experience at least one asthma attack annually. The symptoms of asthma cause significant economic burden on the healthcare systems ($18B in 2008) as well as dramatic impact on the quality of patients' lives. Asthma is characterized by airway inflammation and edema. Recently, the long recognized increase in airway wall microvessel density and expanded blood volume have been suggested to contribute significantly to lung function. This project combines the recognized expertise of Professor Elizabeth Wagner, PhD (PI) in pulmonary angiogenesis physiology and Professor Gregory M. Lanza, MD PhD (PD/PI), whose nanomedicine-based molecular imaging and therapy is well known, particularly in the context of angiogenesis in cancer and atherosclerosis. The overarching hypotheses of this proposal are to use nanomedicine approach to noninvasively characterize bronchial angiogenesis (new vessel formation), to deliver acute antiangiogenic therapy to reduce airway remodeling and improve pulmonary function, and to maintain the acute benefits of this new treatment with standard-of-care low dose steroids. PUBLIC HEALTH RELEVANCE: Asthma is pathologically characterized by airway structure remodeling resulting from damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, and basement membrane thickening. Increases in the number and size of vessels within the airway wall have long been recognized as an element of asthma remodeling, occurring in mild, moderate, and severe asthmatic lungs of patients young and old. However, recent studies now point to a functional relationship between the severity of chronic asthma and increasing microvessel density, suggesting that microvascular blood volume contributes significantly to airway obstruction. The overarching hypotheses of this proposal are that nanomedicine approach can be used effectively: 1) to noninvasively quantify bronchial angiogenesis, 2) to deliver acute antiangiogenic therapy to reduce airway remodeling and improve pulmonary function, and 3) to maintain the acute benefits of antiangiogenic treatment with low dose steroids. This nanomedicine approach to asthma employs quantitative image stratification and targeted prodrug nanotherapy in conjunction with current standard of care drugs to offer a clinically translatable approach to ameliorate the progression of moderate to severe asthma ultimately to reduce hospitalizations and home health-care costs.