Department of Urology, Nanjing Drum Tower Hospital, Medical School of Nanjing University Nanjing, Jiangsu, 210008, China; Institute of Urology, Nanjing University, Nanjing, Jiangsu, 210008, China.
Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing National Laboratory of Microstructures, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, Jiangsu, 210093, China.
Biomaterials. 2019 Oct;219:119368. doi: 10.1016/j.biomaterials.2019.119368. Epub 2019 Jul 16.
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.
急性肾损伤（AKI）与高死亡率和发病率相关，目前尚无有效治疗方法，这大大增加了慢性肾脏病的风险。基于纳米技术的靶向肾小管的药物递送为 AKI 治疗提供了新策略，但由于肾小球滤过屏障的存在，这仍然具有挑战性。为了解决这一挑战，我们在这里证明，直径为 100nm 的聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（NPs）可以在与肾缺血再灌注损伤初始阶段的肾损伤程度和给药时间相关的程度上选择性地在小鼠损伤肾脏中积累。通过免疫荧光证实，NP 位于肾小管上皮细胞中，这对 AKI 的进展至关重要。利用 PLGA NPs 在缺血再灌注（IR）肾脏中的高积累和肾小管靶向性，我们设计了负载 Oltipraz 的 PLGA NPs（PLGA-Oltipraz NPs）来治疗 IR 诱导的 AKI 和肾纤维化。体外结果表明，与游离 Oltipraz 相比，PLGA-Oltipraz NPs 表现出更高的抗氧化作用，细胞活力提高，丙二醛含量降低，超氧化物歧化酶活性提高。进一步在体内研究了 PLGA-Oltipraz NPs 的治疗效果。用 PLGA-Oltipraz NPs 治疗的 AKI 小鼠在初始阶段表现出肾小管坏死明显减少、胶原沉积减少和肾功能改善，以及在恢复阶段肾纤维化改善。这项研究为 AKI 和纤维化的 PLGA-Oltipraz NPs 治疗建立了一种很有前途的方法。它还揭示了纳米治疗中尺寸选择性 NPs 和药物给药时间窗口的重要性。
