Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy

Neonatal hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Catalase, an antioxidant enzyme, is a promising therapeutic due to its ability to scavenge toxic reactive oxygen species and improve tissue oxygen status. However, upon...

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Main Authors: Andrea Joseph, Chris W. Nyambura, Danielle Bondurant, Kylie Corry, Denise Beebout, Thomas R. Wood, Jim Pfaendtner, Elizabeth Nance
Format: Article
Language:English
Published: MDPI AG 2021-07-01
Series:Pharmaceutics
Subjects:
Online Access:https://www.mdpi.com/1999-4923/13/8/1131
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spelling doaj-a7ff1e24210240c58ca5acb09e70392a2021-08-26T14:12:45ZengMDPI AGPharmaceutics1999-49232021-07-01131131113110.3390/pharmaceutics13081131Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic EncephalopathyAndrea Joseph0Chris W. Nyambura1Danielle Bondurant2Kylie Corry3Denise Beebout4Thomas R. Wood5Jim Pfaendtner6Elizabeth Nance7Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADivision of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADivision of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USADepartment of Chemical Engineering, University of Washington, Seattle, WA 98195, USANeonatal hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Catalase, an antioxidant enzyme, is a promising therapeutic due to its ability to scavenge toxic reactive oxygen species and improve tissue oxygen status. However, upon in vivo administration, catalase is subject to a short half-life, rapid proteolytic degradation, immunogenicity, and an inability to penetrate the brain. Polymeric nanoparticles can improve pharmacokinetic properties of therapeutic cargo, although encapsulation of large proteins has been challenging. In this paper, we investigated hydrophobic ion pairing as a technique for increasing the hydrophobicity of catalase and driving its subsequent loading into a poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticle. We found improved formation of catalase-hydrophobic ion complexes with dextran sulfate (DS) compared to sodium dodecyl sulfate (SDS) or taurocholic acid (TA). Molecular dynamics simulations in a model system demonstrated retention of native protein structure after complexation with DS, but not SDS or TA. Using DS-catalase complexes, we developed catalase-loaded PLGA-PEG nanoparticles and evaluated their efficacy in the Vannucci model of unilateral hypoxic-ischemic brain injury in postnatal day 10 rats. Catalase-loaded nanoparticles retained enzymatic activity for at least 24 h in serum-like conditions, distributed through injured brain tissue, and delivered a significant neuroprotective effect compared to saline and blank nanoparticle controls. These results encourage further investigation of catalase and PLGA-PEG nanoparticle-mediated drug delivery for the treatment of neonatal brain injury.https://www.mdpi.com/1999-4923/13/8/1131hypoxia-ischemiahydrophobic-ion pairingcatalasenanomedicineneonatalmolecular dynamics
collection DOAJ
language English
format Article
sources DOAJ
author Andrea Joseph
Chris W. Nyambura
Danielle Bondurant
Kylie Corry
Denise Beebout
Thomas R. Wood
Jim Pfaendtner
Elizabeth Nance
spellingShingle Andrea Joseph
Chris W. Nyambura
Danielle Bondurant
Kylie Corry
Denise Beebout
Thomas R. Wood
Jim Pfaendtner
Elizabeth Nance
Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
Pharmaceutics
hypoxia-ischemia
hydrophobic-ion pairing
catalase
nanomedicine
neonatal
molecular dynamics
author_facet Andrea Joseph
Chris W. Nyambura
Danielle Bondurant
Kylie Corry
Denise Beebout
Thomas R. Wood
Jim Pfaendtner
Elizabeth Nance
author_sort Andrea Joseph
title Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
title_short Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
title_full Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
title_fullStr Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
title_full_unstemmed Formulation and Efficacy of Catalase-Loaded Nanoparticles for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
title_sort formulation and efficacy of catalase-loaded nanoparticles for the treatment of neonatal hypoxic-ischemic encephalopathy
publisher MDPI AG
series Pharmaceutics
issn 1999-4923
publishDate 2021-07-01
description Neonatal hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Catalase, an antioxidant enzyme, is a promising therapeutic due to its ability to scavenge toxic reactive oxygen species and improve tissue oxygen status. However, upon in vivo administration, catalase is subject to a short half-life, rapid proteolytic degradation, immunogenicity, and an inability to penetrate the brain. Polymeric nanoparticles can improve pharmacokinetic properties of therapeutic cargo, although encapsulation of large proteins has been challenging. In this paper, we investigated hydrophobic ion pairing as a technique for increasing the hydrophobicity of catalase and driving its subsequent loading into a poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticle. We found improved formation of catalase-hydrophobic ion complexes with dextran sulfate (DS) compared to sodium dodecyl sulfate (SDS) or taurocholic acid (TA). Molecular dynamics simulations in a model system demonstrated retention of native protein structure after complexation with DS, but not SDS or TA. Using DS-catalase complexes, we developed catalase-loaded PLGA-PEG nanoparticles and evaluated their efficacy in the Vannucci model of unilateral hypoxic-ischemic brain injury in postnatal day 10 rats. Catalase-loaded nanoparticles retained enzymatic activity for at least 24 h in serum-like conditions, distributed through injured brain tissue, and delivered a significant neuroprotective effect compared to saline and blank nanoparticle controls. These results encourage further investigation of catalase and PLGA-PEG nanoparticle-mediated drug delivery for the treatment of neonatal brain injury.
topic hypoxia-ischemia
hydrophobic-ion pairing
catalase
nanomedicine
neonatal
molecular dynamics
url https://www.mdpi.com/1999-4923/13/8/1131
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