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