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

The ß2 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.

Design, Development, Physicochemical Characterization, and In Vitro Drug Release of Formoterol PEGylated PLGA Polymeric Nanoparticles.

Polymeric nanoparticles' drug delivery systems represent a promising platform for targeted controlled release since they are capable of improving the bioavailability and tissue localization of drugs compared to traditional means of administration. Investigation of key parameters of nanoparticle preparation and their impact on performance, such as size, drug loading, and sustained release, is critical to understanding the synthesis parameters surrounding a given nanoparticle formulation. This comprehensive and systematic study reports for the first time and focuses on the development and characterization of formoterol polymeric nanoparticles that have potential application in a variety of acute and chronic diseases. Nanoparticles were prepared by a variety of solvent emulsion methods with varying modifications to the polymer and emulsion system with the aim of increasing drug loading and tuning particle size for renal localization and drug delivery. Maximal drug loading was achieved by amine modification of polyethylene glycol (PEG) conjugated to the poly(lactic-co-glycolic acid) (PLGA) backbone. The resulting formoterol PEGylated PLGA polymeric nanoparticles were successfully lyophilized without compromising size distribution by using either sucrose or trehalose as cryoprotectants. The physicochemical characteristics of the nanoparticles were examined comprehensively, including surface morphology, solid-state transitions, crystallinity, and residual water content. In vitro formoterol drug release characteristics from the PEGylated PLGA polymeric nanoparticles were also investigated as a function of both polymer and emulsion parameter selection, and release kinetics modeling was successfully applied.

Formoterol PLGA-PEG Nanoparticles Induce Mitochondrial Biogenesis in Renal Proximal Tubules.

Formoterol is a long-acting ß2 agonist (LABA). Agonism of the ß2-adrenergic receptor by formoterol is known to stimulate mitochondrial biogenesis (MB) in renal proximal tubules and recover kidney function. However, formoterol has a number of cardiovascular side effects that limits its usage. The goal of this study was to design and develop an intravenous biodegradable and biocompatible polymeric nanoparticle delivery system that targets formoterol to the kidney. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) nanoparticles containing encapsulated formoterol were synthesized by a modified single-emulsion solvent evaporation technique resulting in nanoparticles with a median hydrodynamic diameter of 442 + 17 nm. Using primary cell cultures of rabbit renal proximal tubular cells (RPTCs), free formoterol, encapsulated formoterol polymeric nanoparticles, and drug-free polymeric nanoparticles were biocompatible and not cytotoxic over a wide concentration range. In healthy male mice, polymeric nanoparticles were shown to localize in tubules of the renal cortex and improved the renal localization of encapsulated formoterol compared to the free formoterol. At a lower total formoterol dose, the nanoparticle localization resulted in increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the master regulator of MB, and increased electron transport chain proteins, markers of MB. This was confirmed by direct visual quantification of mitochondria and occurred with both free formoterol and the encapsulated formoterol polymeric nanoparticles. At the same time, localization of nanoparticles to the kidneys resulted in reduced induction of MB markers in the heart. These new nanoparticles effectively target formoterol to the kidney and successfully produce MB in the kidney.