Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

Abstract

Abstract-Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH. Key Words: pulmonary hypertension Ⅲ nanotechnology Ⅲ pitavastatin Ⅲ inflammation Ⅲ leukocytes P ulmonary artery hypertension (PAH) is an intractable disease of the small PAs resulting in progressive increases in pulmonary vascular resistance, right ventricular (RV) failure, and ultimately premature death. 1,2 Mortality from PAH remains high, even after introduction of vasodilator therapies such as prostacyclin infusion, endothelin receptor antagonists, and phosphodiesterase inhibitors (which have raised the 5-year survival rate to Ϸ50%). Although these drugs were originally developed for non-PAH vascular diseases, they were introduced into treatment for clinical PAH on the basis of the vasodilator hypothesis. Therefore, a new idea that might lead to a breakthrough curative treatment for PAH is urgently needed.In addition to vasoconstriction, other multiple factors (endothelial injury/apoptosis, obstructive vascular remodeling, proliferation, and inflammation) play an important role in the mechanism of PAH. 1,2 Therefore, we hypothesized that a controlled, local delivery system targeting a battery of those pathogenic factors intrinsic to PAH pathology would be a favorable therapeutic approach with high translational potential to clinical medicine. In this respect, we focused on the vasculoprotective effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the so-called statins. Stati...

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…At least 30 studies have reported beneficial effects from this drug class in a range of animal models (Chen et al, 2011;Dai & Wu, 2011;DeMarco & Habibi, 2009;Gao, Zhu, Shi, & Jing, 2010;RE Girgis, Li, Zhan, & Garcia, 2003;R. E. Girgis et al, 2007;Guerard et al, 2006;Hsu et al, 2009;Ikeda, Nakamura, Akagi, & Kusano, 2010;Kuang, Wang, Pang, Huang, & Burg, 2010;Laudi et al, 2007;M.…”

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation

“…[14][15][16][17] We recently reported that nanoparticle-mediated delivery of pitavastatin showed significant therapeutic effects on pulmonary arterial hypertension, 18) restenosis, 19) ischemia-reperfusion injury, 20) and atherosclerosis 21) in animals by inhibiting the MCP1-CCR2 pathway. Because PLGA nanoparticles are delivered selectively to inflammatory cells (mainly monocytes) after intravenous administration, 21,22) it is suggested that monocyte-mediated inflammation plays an important role in the mechanism by which pitavastatin-NP exerted beneficial effects in these previous studies.…”

“…Because PLGA nanoparticles are delivered selectively to inflammatory cells (mainly monocytes) after intravenous administration, 21,22) it is suggested that monocyte-mediated inflammation plays an important role in the mechanism by which pitavastatin-NP exerted beneficial effects in these previous studies. [18][19][20][21] Therefore, in the present study, we used a mouse model of post-infarct LV remodeling and tested the hypothesis that 1) PLGA nanoparticles are selectively delivered to inflammatory cells (mainly activated monocytes) and 2) the nanoparticlemediated targeting of pitavastatin to these inflammatory cells after establishment of MI protects the heart from LV remodeling by inhibiting recruitment of inflammatory monocytes to the infarcted heart.…”

Intratracheal instillation of ethyl pyruvate nanoparticles prevents the development of shunt-flow-induced pulmonary arterial hypertension in a rat model

“…The advantages of NP-mediated drug-delivery systems for the treatment of lung diseases, including PAH, have also been confirmed in other studies. 40,41 According to our prior experiment, the in vitro release profile of EP-NPs showed sustained release of 85% EP for at least 168 hours, with a small burst release. In the current in vivo experiments, fluorescence was faint 7 days after FITC-NP administration (Figure 2).…”

“…This agrees with a previous study, in which a lactide/glycolide copolymer (PLGA) used as a carrier for intratracheal instillation for 21 days resulted in no toxicologic reactions. 41 Nonetheless, the long-term safety and therapeutic effects of an NP-mediated EP system in PAH should be explored in further studies. In addition, the accumulation or clearance rate of polymeric materials from the lungs over time should be taken into account in providing more information about the use of such a system.…”