Department of Pharmacology and Toxicology, The University of Arizona R. Ken Coit College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona, USA.
Department of Pharmacology and Toxicology, The University of Arizona R. Ken Coit College of Pharmacy, Skaggs Pharmaceutical Sciences Center, Tucson, Arizona, USA; The University of Arizona College of Medicine, Tucson, Arizona, USA; The University of Arizona, BIO5 Institute, Tucson, Arizona, USA.
Kidney Int. 2022 Nov;102(5):1073-1089. doi: 10.1016/j.kint.2022.05.032. Epub 2022 Jun 30.
The β adrenergic receptor agonist, formoterol, is an inducer of mitochondrial biogenesis and restorer of mitochondrial and kidney function in acute and chronic models of kidney injury. Unfortunately, systemic administration of formoterol has the potential for adverse cardiovascular effects, increased heart rate, and decreased blood pressure. To minimize these effects, we developed biodegradable and biocompatible polymeric nanoparticles containing formoterol that target the kidney, thereby decreasing the effective dose, and lessen cardiovascular effects while restoring kidney function after injury. Male C57Bl/6 mice, treated with these nanoparticles daily, had reduced ischemia-reperfusion-induced serum creatinine and kidney cortex kidney injury molecule-1 levels by 78% and 73% respectively, compared to control mice six days after injury. With nanoparticle therapy, kidney cortical mitochondrial number and proteins reduced by ischemic injury, recovered to levels of sham-operated mice. Tubular necrosis was reduced 69% with nanoparticles treatment. Nanoparticles improved kidney recovery even when the dosing frequency was reduced from daily to two days per week. Finally, compared to treatment with formoterol-free drug alone, these nanoparticles did not increase heart rate nor decrease blood pressure. Thus, targeted kidney delivery of formoterol-containing nanoparticles is an improvement in standard formoterol therapy for ischemia-reperfusion-induced acute kidney injuries by decreasing the dose, dosing frequency, and cardiac side effects.
β肾上腺素能受体激动剂福莫特罗是线粒体生物发生的诱导剂，可恢复急性和慢性肾损伤模型中的线粒体和肾功能。不幸的是，福莫特罗全身给药具有潜在的不良心血管作用，可导致心率增加和血压降低。为了最小化这些作用，我们开发了含有福莫特罗的可生物降解和生物相容的聚合物纳米颗粒，将其靶向肾脏，从而降低有效剂量，并减轻心血管作用，同时在损伤后恢复肾功能。与对照组相比，每天接受这些纳米颗粒治疗的雄性 C57Bl/6 小鼠在损伤后 6 天，缺血再灌注诱导的血清肌酐和肾皮质肾损伤分子 1 水平分别降低了 78%和 73%。与纳米颗粒治疗相比，缺血性损伤导致的肾皮质线粒体数量和蛋白质减少恢复到假手术组小鼠的水平。肾小管坏死减少了 69%。即使将给药频率从每天减少到每周两次，纳米颗粒治疗也能改善肾脏恢复。最后，与单独使用不含福莫特罗的药物相比，这些纳米颗粒不会增加心率或降低血压。因此，将含有福莫特罗的纳米颗粒靶向递送至肾脏，可通过降低剂量、给药频率和心脏副作用，改善缺血再灌注引起的急性肾损伤的标准福莫特罗治疗。
