ABSTRACT
Treating Chronic Obstructive Lung DiseasesWe and others have recently discussed in detail the application of novel nanosystems in treating various respiratory conditions such as CF, COPD, allergy, asthma, and lung cancer [18-27]. We anticipate that stringent preclinical evaluation and standardization of novel disease-specific nanotherapeutic strategies hold a promise for clinical application and translation. Drug or gene delivery via nanosystems face various disease-related pathophysiological challenges. Hence, nanosystems specifically designed to circumvent these challenges in the specific disease state need to be carefully designed [18, 19]. On airway deposition, nanoparticles encounter various physiochemical and biological barriers such as the catabolic enzymes and mucus in the tracheobronchial region and macrophages in the alveolar region. In the peripheral region of the lung, particles must be able to dissolve and diffuse through the epithelial barrier into the blood stream. Large-size particles that are unable to do so are subject to phagocytosis by alveolar macrophages. However, this property of large particles can be tailored to selectively target the drug to
macrophages in disease states such as COPD-emphysema [19]. On the contrary, small-or ultrafine-nanoparticles have the tendency to accumulate in the airway. The surface coating on the nanosystems can be used to avoid their aggregation while promoting clearance. Despite these hindrances, the lung is an attractive target for nanoparticle-mediated drug delivery due to its capacity to provide a noninvasive means for local lung delivery as well as high systemic bioavailability. A large surface area for absorption and limited proteolytic activity makes the pulmonary route an excellent system for local delivery of drugs for the treatment of various obstructive lung diseases, such as asthma, COPD-emphysema, CF, and as other respiratory conditions, including pulmonary hypertension and lung cancer. It is advantageous to treat these diseases locally since the drug is able to directly deposit itself at the disease site, avoiding rapid metabolism. As an example, nanoparticle-mediated drug delivery to the lung epithelium eliminates potential side effects caused by high systemic concentrations and reduces costs by use of both small doses and targeted drug activity [28]. Moreover, the nano-based systems are ideal for targeted delivery of drugs to specific inflammatory cells, such as alveolar macrophages, neutrophils, or T cells, for the treatment of obstructive lung diseases, as we recently discussed [19]. Obstructive lung diseases such as COPD represent one of the major global causes of disability and death. It is estimated that COPD will become the third-leading cause of death by 2020 [5]. As we recently discussed in detail, the major challenges in the delivery and therapeutic efficacy of nanodelivery systems in chronic obstructive lung diseases are severe inflammation and mucous hypersecretion [19-23], which are exacerbated by infection or components of CS [21, 22, 24-26]. The chronic stage of these diseases is associated with widespread damage to the airway cells due to excessive inflammation, apoptosis and defective repair mechanisms [22, 24, 26, 27]. Controlling chronic inflammatory-oxidative responses is an acceptable or available therapy, although the challenge is the targeted and controlled delivery of drugs [28]. We have also recently discussed in detail that in spite of the wide application of nano-based drug delivery systems in chronic obstructive airway diseases and a variety of other pulmonary conditions, very few are tested till date [5, 7, 29, 30]. As an example, we have recently discussed the
application of epithelial-targeted nanoparticles to control neutrophil chemotaxis, fibrosis, and protease-mediated chronic emphysema
(Fig. 1.1) [19]. mediatedchronicemphysema(Fig.1.1)[19].
