Nanotheranostics 2022; 6(2):215-229. doi:10.7150/ntno.62351 This issue

Research Paper

Lipid nitroalkene nanoparticles for the focal treatment of ischemia reperfusion

Gary Z Yu1, Thiruganesh Ramasamy1, Marco Fazzari2, Xucai Chen1, Bruce Freeman2, John J Pacella

1. Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA;
2. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Yu GZ, Ramasamy T, Fazzari M, Chen X, Freeman B, Pacella JJ. Lipid nitroalkene nanoparticles for the focal treatment of ischemia reperfusion. Nanotheranostics 2022; 6(2):215-229. doi:10.7150/ntno.62351. Available from https://www.ntno.org/v06p0215.htm

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Abstract

Graphic abstract

Rationale: The treatment of microvascular obstruction (MVO) using ultrasound-targeted LNP cavitation (UTC) therapy mechanically relieves the physical obstruction in the microcirculation but does not specifically target the associated inflammatory milieu. Electrophilic fatty acid nitroalkene derivatives (nitro-fatty acids), that display pleiotropic anti-inflammatory signaling and transcriptional regulatory actions, offer strong therapeutic potential but lack a means of rapid targeted delivery. The objective of this study was to develop nitro-fatty acid-containing lipid nanoparticles (LNP) that retain the mechanical efficacy of standard LNP and can rapidly target delivery of a tissue-protective payload that reduces inflammation and improves vascular function following ischemia-reperfusion.

Methods: The stability and acoustic behavior of nitro-fatty acid LNP (NO2-FA-LNP) were characterized by HPLC-MS/MS and ultra-high-speed microscopy. The LNP were then used in a rat hindlimb model of ischemia-reperfusion injury with ultrasound-targeted cavitation.

Results: Intravenous administration of NO2-FA-LNP followed by ultrasound-targeted LNP cavitation (UTC) in both healthy rat hindlimb and following ischemia-reperfusion injury showed enhanced NO2-FA tissue delivery and microvascular perfusion. In addition, vascular inflammatory mediator expression and lipid peroxidation were decreased in tissues following ischemia-reperfusion revealed NO2-FA-LNP protected against inflammatory injury.

Conclusions: Vascular targeting of NO2-FA-LNP with UTC offers a rapid method of focal anti-inflammatory therapy at sites of ischemia-reperfusion injury.

Keywords: ultrasound-targeted lipid nanoparticle cavitation, microvascular obstruction, acute myocardial infarction, inflammation, nitro-fatty acid, nitroalkene