Development of Angiotensin II Receptor Blocker Nanoparticles for an Inhaled Therapeutic Treatment of COPD via TGF-Beta Antagonism
Embargo until
2021-05-01
Date
2019-05-13
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Johns Hopkins University
Abstract
Chronic obstructive pulmonary disease (COPD) is a widespread, progressive lung disease that is characterized by airspace enlargement, inflammation, sputum production, and airway remodeling. Current treatments target and manage symptoms while failing to treat the underlying cause of COPD. Previous studies have shown that overexpression of transforming growth factor beta (TGF-β) is a primary factor in the pathogenesis of COPD. We have previously shown that angiotensin II receptor blockers (ARBs) can antagonize TGF-β expression via angiotensin II type 1 receptor blockage. We have successfully developed a localized treatment for cigarette-smoke induced lung injury through TGF-β antagonization using the ARB Telmisartan (TEL). Here, I have begun the investigation into four ARBs, formulated as nanocrystals, for inhaled localized treatment of COPD. We hypothesized that by using F127, a surfactant known as pluronic polymer we can develop muco-inert nanocrystals with increased retention time, improved pharmacokinetics, and therapeutic efficacy while reducing administration concentrations. Four ARBs were formulated as nanocrystal with three pluronic polymers. Surface characterization was controlled via choice of pluronic polymer. I found that pluronic polymer F127 provided ideal surface stabilization and improved retention time through assumed mucus penetration and macrophage uptake resistance. ARB nanocrystals {ARB-NC’s) were shown to have a favorable linear release profile in vitro as well as drug activity unaffected by the coating. In vivo investigation suggest F127/ARBs may have improved pharmacokinetics, but additional research is required to confirm. Finally, an accurate COPD murine model was used to test for TGF-β expression antagonism and therapeutic effect of inhaled F127/TEL nanocrystals both of which showed positive effect. Thus, I conclude that F127/ARB nanocrystals can provide a therapeutic treatment for COPD and further investigation should continue with the ARBs used in this study and others currently on the market.
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Keywords
angiotensin
receptor
blocker
nanocrystal
COPD
chronic obstructive pulmonary disease