Kidney-Targeted Nanoparticle Delivery of Formoterol Mitigates Diabetic Kidney Disease without Adverse Cardiac Effects

Mitochondrial dysfunction plays a critical role in the progression of diabetic kidney disease (DKD). Previous research indicates that the FDA-approved β2-adrenergic receptor agonist and bronchodilator formoterol are efficacious at restoring mitochondrial function and slowing DKD progression. Unfortunately, β2-adrenergic receptor antagonists have been shown to result in cardiovascular toxicity. To mitigate these negative effects while maintaining the therapeutic capabilities of formoterol, we developed formoterol-containing renally targeted polymeric nanoparticles (NPs). Biocompatible NPs were synthesized (300-400 nm), and efficient internalization by renal proximal tubule cells was confirmed. NPs were administered to SKH-1 Elite mice, and renal accumulation was observed within 1h and retained for 144h. To determine the therapeutic potential of this strategy for DKD treatment, BTBR ob/ob mice, a model of type 2 diabetes, were administered formoterol free drug (FFD) or formoterol-containing NPs (FNP) for 8 weeks. FFD and FNP administration slowed progression of DKD, as evidenced by reduced blood glucose levels, urine output, and the albumin:creatinine ratio. FNPs also decreased glomerular hyperfiltration, mesangial expansion, glomerulosclerosis, and tubular inflammation in BTBR ob/ob mice. Importantly, unlike FFD, the chronic administration of NP-encapsulated formoterol did not show evidence of cardiovascular toxicity. This approach introduces novel renally targeted, formoterol-containing polymeric NPs as a potential therapeutic for hyperglycemia-induced DKD.