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

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Abstract

Formoterol is a long-acting β2 agonist (LABA). Agonism of the β2-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.

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Acknowledgements

The authors gratefully acknowledge University of Arizona funding. The authors are grateful to Yelena Feinstein and Krishna Parsawar for assistance with the mass spectrometry as well as the laboratory of Dr. Jianqin Lu for use of their rotary evaporator.

Funding

This work was funded in part by support from the University of Arizona College of Pharmacy as well as the Southwest Environmental Health Sciences Center (P30 ES006694).

All SEM images and data were collected in the W.M. Keck Center for Nano-Scale Imaging in the Department of Chemistry and Biochemistry at the University of Arizona with funding from the W.M. Keck Foundation Grant.

All TEM images and data were collected in The University of Arizona, Imaging Cores - Life Sciences North with funding from the NIH (S10 OD011981) and assistance from Dr. William A. Day.

Mass Spectra were acquired by the Arizona Analytical and Biological Mass Spectrometry Core Facility supported by NIEHS grant ES06694 to the Southwest Environmental Health Sciences Center, NIH/NCI grant CA023074 to the Arizona Cancer Center, and by the BIO5 Institute of the University of Arizona.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, The University of Arizona College of Pharmacy, Tucson, Arizona, 85721, USA

    Ernest L. Vallorz, Karen Blohm-Mangone, Rick G. Schnellmann & Heidi M. Mansour

  2. Department of Medicine, The University of Arizona College of Medicine, Tucson, Arizona, 85724, USA

    Rick G. Schnellmann & Heidi M. Mansour

  3. BIO5 Institute, The University of Arizona, Tucson, Arizona, 85719, USA

    Rick G. Schnellmann & Heidi M. Mansour

  4. Southern Arizona VA Health Care System, Tucson, Arizona, 85723, USA

    Rick G. Schnellmann

  5. Colleges of Pharmacy & Medicine, The University of Arizona, 1703 E. Mabel St, Tucson, Arizona, 85721-0207, USA

    Heidi M. Mansour

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  1. Ernest L. Vallorz
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Contributions

Ernest L. Vallorz: Conceptualization, methodology, data acquisition, interpretation, analysis, writing — original draft. Karen Blohm-Mangone: methodology, data acquisition. Rick G. Schnellmann: conceptualization; methodology; interpretation; analysis; writing — review and editing; resources; funding acquisition; resources; supervision; project administration. Heidi M. Mansour: conceptualization; methodology; interpretation; analysis; writing — review and editing; resources; supervision; project administration

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Correspondence to Heidi M. Mansour.

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Vallorz, E.L., Blohm-Mangone, K., Schnellmann, R.G. et al. Formoterol PLGA-PEG Nanoparticles Induce Mitochondrial Biogenesis in Renal Proximal Tubules. AAPS J 23, 88 (2021). https://doi.org/10.1208/s12248-021-00619-4

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