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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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The shape effect on polymer nanoparticle transport in a blood vessel
Nanoparticle therapeutic delivery is influenced by many factors including physical, chemical, and biophysical properties along with local vascular conditions. In recent years, nanoparticles of various shapes have been fabricated and have shown significant impact on transport efficiency. Identification of which nanoparticle shape helps to improve the therapeutic delivery process allows for enhanced therapeutic effects, yet is hard to be quantified in vivo due to the complex nature of the in vivo environment. In this work, we turn to biological models as a guide for informing improved nanoparticle therapeutic delivery, and quantify the contribution of various factors on delivery efficiency. Here we show that with a mimetic blood vessel, improved therapeutic delivery is achieved using long filamentous rod nanoparticles under low pressure conditions. When considering medium pressure conditions, a combination of nanoparticle shapes presents improved therapeutic delivery over the treatment time-course starting with long filamentous rod nanoparticles, followed by short rod nanoparticles. Conditions of high pressure required a combination of short rod nanoparticles, followed by spherical nanoparticles to achieve enhanced therapeutic delivery. Overall, improvement of therapeutic delivery via nanoparticle carriers is likely to require a combination of nanoparticle shapes administered at different times over the treatment time-course, given patient specific conditions.
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- Award ID(s):
- 1701136
- PAR ID:
- 10057782
- Date Published:
- Journal Name:
- RSC Advances
- Volume:
- 8
- Issue:
- 15
- ISSN:
- 2046-2069
- Page Range / eLocation ID:
- 8089 to 8100
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8RA00033F
