Kidney targeting of formoterol containing polymeric nanoparticles improves recovery from ischemia reperfusion-induced acute kidney injury in mice

Abstract

The β₂ 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.

Keywords: acute kidney injury; drug development; mitochondrial biogenesis; nanoparticle.