title: Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration.
abstract: Excessive production of superoxide (O2(-)) in the central nervous system has been widely implicated in the pathogenesis of cardiovascular diseases, including chronic heart failure and hypertension. In an attempt to overcome the failed therapeutic impact of currently available antioxidants in cardiovascular disease, we developed a nanomedicine-based delivery system for the O2(-)-scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD), in which CuZnSOD protein is electrostatically bound to a poly-l-lysine (PLL50)-polyethylene glycol (PEG) block copolymer to form a CuZnSOD nanozyme. Various formulations of CuZnSOD nanozyme are covalently stabilized by either reducible or nonreducible crosslinked bonds between the PLL50-PEG polymers. Herein, we tested the hypothesis that PLL50-PEG CuZnSOD nanozyme delivers active CuZnSOD protein to neurons and decreases blood pressure in a mouse model of angiotensin II (AngII)-dependent hypertension. As determined by electron paramagnetic resonance spectroscopy, nanozymes retain full SOD enzymatic activity compared to native CuZnSOD protein. Nonreducible CuZnSOD nanozyme delivers active CuZnSOD protein to central neurons in culture (CATH.a neurons) without inducing significant neuronal toxicity. Furthermore, in vivo studies conducted in adult male C57BL/6 mice demonstrate that hypertension established by chronic subcutaneous infusion of AngII is significantly attenuated for up to 7 days after a single intracerebroventricular injection of nonreducible nanozyme. These data indicate the efficacy of nonreducible PLL50-PEG CuZnSOD nanozyme in counteracting excessive O2(-) and decreasing blood pressure in AngII-dependent hypertensive mice after central administration. Additionally, this study supports the further development of PLL50-PEG CuZnSOD nanozyme as an antioxidant-based therapeutic option for hypertension.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Krupa
authors.initials: K
authors.lastname: Savalia
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanomedicine in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Devika S
authors.initials: DS
authors.lastname: Manickam
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Rosenbaugh
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; School of Allied Health Professionals, and University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Iman M
authors.initials: IM
authors.lastname: Ahmad
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanomedicine in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: mczimmerman@unmc.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D002490:Central Nervous System; D016503:Drug Delivery Systems; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D011092:Polyethylene Glycols; D011108:Polymers; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D011108:Polymers; D013481:Superoxides; D000804:Angiotensin II; D011092:Polyethylene Glycols; D013482:Superoxide Dismutase
keywords: Angiotensin II; Free radicals; Hypertension; Nanomedicine; Neurons; Superoxide; Superoxide dismutase