Objective: To investigate the antifibrotic effect of the combination of a PPARγ agonist-loaded nanoparticle-microbubble complex with ultrasound (US) exposure on renal interstitial fibrosis (RIF).
Materials and Methods: Polylactide-co-glycolide (PLGA) nanoparticles were used to load PPARγ agonist (rosiglitazone, RSG) and prepare PLGA-RSG nanoparticles (PLNPs-RSG); then, a novel complex between PLNPs-RSG and SonoVue microbubbles (MBs) (PLNPs-RSG-MBs) was prepared. The size distribution, zeta potentials, RSG-loading capacity and entrapment efficiency were measured, and the release of RSG was assessed using a UV-vis spectrophotometer. The in vitro cytotoxicity and in vivo systemic toxicity assays were performed. The cellular uptake assessment was performed using a confocal laser scanning microscope (CLSM). The in vivo biodistribution assessment was performed using fluorescence imaging with a near-infrared (NIR) imaging system. Furthermore, this complex was administered to a unilateral ureteral obstruction (UUO) rat model with the assistance of US exposure to investigate the antifibrotic effect.
Results: This PLNPs-RSG-MBs complex had a size of 2199.5± 988.1 nm and a drug-loading efficiency of 28.5%. In vitro cytotoxicity and in vivo systemic toxicity assays indicated that the PLNPs-RSG-MBs complex displayed excellent biocompatibility. In addition, the complex showed high cellular uptake efficiency in vitro and kidney-targeting ability in vivo. In a UUO rat model, the combination of the PLNPs-RSG-MBs complex with US exposure significantly reduced collagen deposition and successfully attenuated renal fibrosis.
Conclusion: The combination of the PLNPs-RSG-MBs complex with US exposure may be a promising approach for the treatment of RIF.
Keywords: ultrasound, nanoparticles, microbubbles, peroxisome proliferator-activated receptor, renal interstitial fibrosis