Targeted drug delivery to emphysematous lungs: Inhibition of MMPs by doxycycline loaded nanoparticles

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in U.S. following cancer and heart disease. Current hypothesis regarding mechanism of emphysema suggest that chronic exposure to cigarette smoke and particulate matter causes irritation in the alveoli and this triggers an inflammatory response. This response attracts a host of inflammatory cells like macrophages, neutrophils, and lymphocytes. Cytokines, reactive oxygen species, prostaglandins, leukotrienes, proteases mediate the progression of the disease [1, 2]. Of particular interest to this research is emphysema in COPD patients. This results in poorly reversible airway obstruction due to the destruction of alveoli and elastin fibers in the lung [3, 4]. Loss of elastin in the lungs correlates to loss of lung function in patients [5, 6]. Currently available treatments for COPD aim at only providing temporary relief to the patients by mitigating inflammation or by the action of bronchodilators [7–10]. Corticosteroids have been shown to have no anti-inflammatory effect in COPD patients [11]. None of the available treatments has shown promising effect on treating the disease yet. Matrix metalloproteinases (MMPs) have received a lot of attention in emphysema research with their key role in damaging elastin fibers, thus contributing to the enlargement of air spaces and loss of elastic recoil in the lungs [12]. Use of MMP inhibitors in COPD has been explored in animal models [13, 14] but there is always the risk of off-targeting of MMPs with the systemic delivery of these drugs [15]. Doxycycline is one potential broad-spectrum MMP inhibitor. It is the only FDA approved MMP inhibitor that is widely available. It is shown to inhibit early inflammation in diseases like pulmonary fibrosis [16, 17] by reducing MMP activity in smooth muscle cells [18, 19]. It can also be used as a treatment for COPD exacerbations. While the exact process of MMP inhibition by doxycycline (or tetracyclines in general) is not known, it is believed that this happens by both direct inhibition of MMPs and by inhibiting their expression. Direct inhibition involves chelation of bivalent ions like Ca2+ or Zn2+ which are essential for the functioning of these enzymes [20]. Liu et al., [18] observed reduced MMP-2 mRNA half life but steady state MMP-2 mRNA production by human smooth muscle cells (SMCs) in vitro, there by proposing a post-transcriptional destabilization of MMP-2 mRNA by doxycycline. Additionally, doxycycline specifically targets endothelial cells where it inhibits MMP synthesis [21]. Nanoparticles have recently been investigated as potential drug delivery systems to the lungs because of various advantages they offer [22]. In order to increase the specificity and availability of nanoparticles loaded with drugs, use of monoclonal antibodies to specific biomolecules within the lungs has been suggested as a potential opportunity but has been poorly explored [23, 24]. Inhalation of drug-loaded particulates via aerosols is common way to deliver drugs to the lungs. However, inhalation of drugs to treat pulmonary disorders has certain limitations. The fate of an inhaled particle depends on its size, anatomy of airways and ventilatory parameters [25–27]. Despite the plethora of drug delivery opportunities available, there is a greater need for a highly effective delivery method, which combines an active targeting formulation and consistent local release of a drug for enhanced therapeutic effect. In this paper, we investigated a novel method of drug delivery, in a rat elastase model of emphysema, with a systemic injection of nanoparticles loaded with doxycycline, an MMP inhibitor. We took advantage of elastin damage in emphysema and tested our hypothesis that anti-elastin coated bovine serum albumin (BSA) nanoparticles injected intravenously will target the lungs and will release doxycycline over a period to suppress MMP activity in lungs.