Targeted Delivery of Drug Loaded Albumin Nanoparticles to Emphysematous Lungs to Preserve Elastin and Mitigate Matrix Metalloproteinase Activity

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in U.S. following cancer and heart disease. COPD is an umbrella term for two chronic pathological conditions, namely chronic bronchitis and emphysema that are seen in patients. According to American Lung Association, 12.7 million Americans have been diagnosed with COPD, while 24 million people have impaired lung function, considered as underdiagnosed for the disease resulting in a huge cost to the nation of about $50 billion. Emphysema is an airway disease in which inflammation mediated elastin damage occurs over a long period. Owing to protease/ anti-protease imbalance because of this chronic inflammation, various elastases can degrade elastin. Loss of elastin in the lungs has been shown to correlate with loss of lung function in patients. Currently available treatments for COPD aim at only providing temporary relief to the patients by mitigating inflammation or by the action of bronchodilators. Elastin breakdown and chronic inflammatory conditions are hallmark of emphysema. We have developed unique way to deliver nanoparticles tagged with elastin antibody that recognizes degraded elastin in the cardiovascular disease sites. In this research, we have shown that this targeted delivery can be extended to emphysematous lungs to deliver doxycycline and pentagalloyl glucose (PGG) in an attempt to inhibit matrix metalloproteinase (MMP) activity and to preserve elastin in the lung tissue using both in vitro and in vivo approaches

Targeted delivery of pentagalloyl glucose inhibits matrix metalloproteinase activity and preserves elastin in emphysematous lungs

Abstract Background Elastin degradation has been established as one of the driving factors of emphysema. Elastin-derived peptides (EDPs) are shown to act as a chemoattractant for monocytes. Effectively shielding elastin from elastolytic damage and regenerating lost elastin are two important steps in improving the mechanical function of damaged lungs. Pentagalloyl glucose (PGG) has been shown to preserve elastin in vascular tissues from elastolytic damage in vivo and aid in elastin deposition in vitro. Methods We created emphysema by elastase inhalation challenge in mice. Albumin nanoparticles loaded with PGG, conjugated with elastin antibody, were delivered to target degraded elastin in lungs. We investigated matrix metalloproteinase-12 activity and lung damage by measuring dynamic compliance and tidal volume changes. Results Ex-vivo experiments demonstrated elastin preservation in PGG treated samples compared to controls. Inhaled nanoparticles conjugated with elastin antibody retained for extended periods in lungs. Further, mice treated with PGG nanoparticles showed a significant suppression of MMP-12 activity measured in the lungs. We observed suppression of emphysema in terms of dynamic lung compliance and tidal volume change compared to the control group. The histological examination further confirmed elastin preservation in the lungs. Conclusion These results demonstrate successful targeted delivery of nanoparticles loaded with PGG to inhibit MMP-12 activity and preserve elastin in the lungs. Such targeted PGG therapy has potential therapeutic use in the management of emphysema

Season wise malaria cases (PF: <i>Plasmodium falciparum</i>, PV: <i>Plasmodium vivax</i>) in East Siang District of Arunachal Pradesh, India.

<p>Season wise malaria cases (PF: <i>Plasmodium falciparum</i>, PV: <i>Plasmodium vivax</i>) in East Siang District of Arunachal Pradesh, India.</p

Month wise <i>Plasmodium vivax</i> (PV) malaria cases in East Siang district of Arunachal Pradesh, India.

<p>Month wise <i>Plasmodium vivax</i> (PV) malaria cases in East Siang district of Arunachal Pradesh, India.</p

Contribution chart of climate variables.

<p>Contribution chart of climate variables.</p

Selected Loading vector’s Matrix.

<p>Selected Loading vector’s Matrix.</p

Climate Drivers on Malaria Transmission in Arunachal Pradesh, India

<div><p>The present study was conducted during the years 2006 to 2012 and provides information on prevalence of malaria and its regulation with effect to various climatic factors in East Siang district of Arunachal Pradesh, India. Correlation analysis, Principal Component Analysis and Hotelling’s <i>T²</i> statistics models are adopted to understand the effect of weather variables on malaria transmission. The epidemiological study shows that the prevalence of malaria is mostly caused by the parasite <i>Plasmodium vivax</i> followed by <i>Plasmodium falciparum</i>. It is noted that, the intensity of malaria cases declined gradually from the year 2006 to 2012. The transmission of malaria observed was more during the rainy season, as compared to summer and winter seasons. Further, the data analysis study with Principal Component Analysis and Hotelling’s <i>T²</i> statistic has revealed that the climatic variables such as temperature and rainfall are the most influencing factors for the high rate of malaria transmission in East Siang district of Arunachal Pradesh.</p></div

Map showing the East Siang district of Arunachal Pradesh, India.

<p>Map showing the East Siang district of Arunachal Pradesh, India.</p

Month wise <i>Plasmodium falciparum</i> (PF) malaria cases in East Siang district of Arunachal Pradesh, India.

<p>Month wise <i>Plasmodium falciparum</i> (PF) malaria cases in East Siang district of Arunachal Pradesh, India.</p

Eigenvalue analysis of climatic factor data (a) eigenvalues (b) CPV.

<p>Eigenvalue analysis of climatic factor data (a) eigenvalues (b) CPV.</p