Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 524, Issue 1-2, Pages 257-267Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2017.03.069
Keywords
Pulmonary arterial hypertension; Rapamycin; Polymer nanoparticles; Drug delivery; Endothelial dysfunction; Vascular permeability
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Funding
- George and Angelina Kostas Research Center for Cardiovascular Nanomedicine
- Instituto Tecnologico y de Estudios Superiores de Monterrey
- Consejo Nacional de Ciencia y Tecnologia (CONACyT) [490202/278979]
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Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(e-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site- specific delivery of therapeutics. (C) 2017 Elsevier B.V. All rights reserved.
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