Size and temporal-dependent efficacy of oltipraz-loaded PLGA nanoparticles for treatment of acute kidney injury and fibrosis

Abstract

Acute kidney injury (AKI) is associated with high mortality and morbidity with no effective treatment available at present, which greatly escalates the risk of chronic kidney disease. Nanotechnology-based drug delivery for targeting renal tubules offers a new strategy for AKI treatment but remains challenging due to the glomerular filtration barrier. To tackle this challenge, here we demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of 100 nm diameter could selectively accumulate in mouse injury kidneys in correlation to the degree of kidney injury and administration time during the initial phase of renal ischemia-reperfusion injury. The NPs were located in renal tubular epithelial cells confirmed by immunofluorescence, which is critical for the progression of AKI. Taking advantage of the high accumulation and renal tubule targeting of the PLGA NPs in the ischemia-reperfusion (IR) kidney, we designed PLGA NPs loaded with Oltipraz (PLGA-Oltipraz NPs) to treat IR-induced AKI and renal fibrosis. In vitro results showed that compared to free Oltipraz, PLGA-Oltipraz NPs displayed a higher antioxidation effect with improved cell viability, lower contents of malondialdehyde, and higher activity of superoxide dismutase. The therapeutic efficacy of PLGA-Oltipraz NPs was further investigated in vivo. Mice with AKI treated with PLGA-Oltipraz NPs exhibited significantly reduced tubular necrosis, less collagen deposition, and better renal function at the initial phase as well as improved renal fibrosis at the recovery phase. This study establishes a promising approach for AKI and fibrosis treatment with PLGA-Oltipraz NPs. It also reveals the importance of size-selective NPs and drug administration time window to nanotherpeutics.

Keywords: Acute renal injury; Drug delivery; Nanomedicine; Nanoparticles; Renal fibrosis.