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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. View Full-Text
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Self‐assembled, ellipsoidal polymeric nanoparticles for intracellular delivery of therapeutics
Abstract Nanoparticle shape has emerged as a key regulator of nanoparticle transport across physiological barriers, intracellular uptake, and biodistribution. We report a facile approach to synthesize ellipsoidal nanoparticles through self‐assembly of poly(glycerol sebacate)‐co‐poly(ethylene glycol) (PGS‐co‐PEG). The PGS‐PEG nanoparticle system is highly tunable, and the semiaxis length of the nanoparticles can be modulated by changing PGS‐PEG molar ratio and incorporating therapeutics. As both PGS and PEG are highly biocompatible, the PGS‐co‐PEG nanoparticles show high hemo‐, immuno‐, and cytocompatibility. Our data suggest that PGS‐co‐PEG nanoparticles have the potential for use in a wide range of biomedical applications including regenerative medicine, stem cell engineering, immune modulation, and cancer therapeutics. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2048–2058, 2018.
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- Award ID(s):
- 1705852
- PAR ID:
- 10067018
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Journal of Biomedical Materials Research Part A
- Volume:
- 106
- Issue:
- 7
- ISSN:
- 1549-3296
- Page Range / eLocation ID:
- p. 2048-2058
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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