Utilizing Nanotechnology for Disease Severity Assessment and Drug Delivery in Chronic Obstructive Pulmonary Disease
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Date
2017-10-27
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Johns Hopkins University
Abstract
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the United States with continuously elevating morbidity and mortality. COPD is a complex progressive disease primarily caused by cigarette smoke (CS) as well as other inhaled pollutants. The disease is characterized by chronic, irreversible obstruction of airflow from the lung, which is resulted from both airspace enlargement (i.e. emphysema), as well as airway inflammation, remodeling, and mucus hypersecretion (chronic bronchitis).
Perturbations in the properties of airway mucus contribute to accelerated lung function decline in patients with COPD, which leads to reduced quality of life and an elevated mortality rate. Alterations in the bulk physicochemical properties of mucus have been widely investigated in an attempt to unravel key factors affecting disease severity. Nonetheless, microstructural characteristics of mucus have not yet been explored in COPD. I first investigated whether the mesh size of spontaneously expectorated COPD sputum, as indicated by muco-inert nanoparticle diffusion, correlated with impaired lung function and altered sputum composition. I found that the diffusion of 100 nm muco-inert nanoparticles could sensitively differentiate microstructural features of sputum samples from cigarette smokers without airway obstruction and COPD patients. Nanoparticle mobility correlated with measurements of lung function as well as sputum solids and mucin content. These findings suggest that sputum microstructure as quantified by muco-inert nanoparticle diffusion may serve as a novel indicator and/or risk factor for COPD severity and progression.
There is currently no cure for COPD. Treatment options are limited to symptom relief and do not arrest or reverse the deterioration in lung function and architecture that accompanies the disease. Elevated transforming growth factor beta (TGF-) signaling is strongly implicated as a key contributor to COPD development and progression. We have previously shown that an orally administered angiotensin receptor blocker (ARB) protected against airspace damage in animal models of COPD via TGF- antagonism. Here I engineered an inhalable drug nanocrystal (NC) formulation based the ARB telmisartan (TEL; TEL-NC) for the localized treatment of COPD. The TEL-NC possess a bio-inert surface coating that promoted colloidal stability and minimized macrophage uptake, and thus, improved the local drug concentration following inhalation compared to both inhaled and orally administered free drug. I then investigated the efficacy of inhaled TEL-NC in two widely explored animal models relevant to COPD. Treatment with TEL-NC provided a protective effect in an acute cigarette smoke (CS)-induced injury model via suppression of TGF- signaling and attenuation of oxidative stress and inflammation. In the tight-skin (TSK) transgenic emphysema model, inhaled TEL-NC provided therapeutic resolution of disease pathogenesis, while orally administered free drug had no therapeutic effect. These findings suggest that inhaled TEL-NC can prevent and/or reverse COPD-related disease manifestation caused by enhanced TGF- signaling.
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Keywords
COPD sputum, multiple particle tracking, muco-inert nanoparticles, inhaled drug delivery, therapeutic nanocrystals,