Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension

Victor Segura-Ibarra, Javier Amione-Guerra, Ana S. Cruz-Solbes, Francisca E. Cara, David A. Iruegas-Nunez, Suhong Wu, Keith A. Youker, Arvind Bhimaraj, Guillermo Torre-Amione, Mauro Ferrari, Harry Karmouty-Quintana, Ashrith Guha, Elvin Blanco

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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(ε-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.

Original languageEnglish (US)
Pages (from-to)257-267
Number of pages11
JournalInternational Journal of Pharmaceutics
Volume524
Issue number1-2
DOIs
StatePublished - May 30 2017

Keywords

  • Drug delivery
  • Endothelial dysfunction
  • Polymer nanoparticles
  • Pulmonary arterial hypertension
  • Rapamycin
  • Vascular permeability

ASJC Scopus subject areas

  • Pharmaceutical Science

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