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Wenjun Shang
Zhengzhou University First Affiliated Hospital
Corresponding Author
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Background: Significant advances have been made in recent years to utilize natural enzymes with antioxidant properties for the treatment of acute kidney injury (AKI). However, these enzymes have limited clinical utility due to their limited cellular uptake, poor pharmacokinetic properties, and suboptimal stability. We prepared a novel biomimetic mineralization approach to overcome these limitations.
Results: Catalase (CAT) and superoxide dismutase (SOD) were encapsulated in a zeolitic imidazolate framework-8 (ZIF-8), then this [email protected]@ZIF-8 complex was anchored with MPEG2000-COOH to yield an MPEG2000[email protected]@ZIF-8 (PSCZ) composite. This composite was then utilized as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI, remarkably improved intracellular enzyme delivery. The PSCZ composite showed a significantly relieve ability of H2O2 induced ROS and prevented apoptosis in HEK293 cells. In vivo, this composite showed a protective effect in the cisplatin-induced AKI mouse model. In addition, PSCZ treatment mitigated renal dysfunction and histological injury, like tubulointerstitial infiltration. RNA sequencing results further confirmed the protective effect of PSCZ and the potential molecular mechanism was revealed. PSCZ treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and inflammatory infiltration of renal tubules. Moreover, PSCZ administration regulated renal injury via the p53 signaling pathway. These renoprotective effects of PSCZ treatment were more potent in CP-AKI mice than those of SOD or CAT alone. This dual-enzyme-embedded metal-organic framework was able to scavenge reactive oxygen species synergistically and effectively.
Conclusion: PSCZ can remarkably improve intracellular enzyme delivery, and it can be used as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI. The ZIF-8-based “armor plating” represents an effective means of shielding enzymes with improved therapeutic utility to guide the precision medicine-based treatment of AKI.
Keywords
metal-organic frameworks, biomimetic mineralization, dual-enzyme cascade, ROS scavenging, acute kidney injury
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Wenjun Shang
Zhengzhou University First Affiliated Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 18 May, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Nanoscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Significant advances have been made in recent years to utilize natural enzymes with antioxidant properties for the treatment of acute kidney injury (AKI). However, these enzymes have limited clinical utility due to their limited cellular uptake, poor pharmacokinetic properties, and suboptimal stability. We prepared a novel biomimetic mineralization approach to overcome these limitations.
Results: Catalase (CAT) and superoxide dismutase (SOD) were encapsulated in a zeolitic imidazolate framework-8 (ZIF-8), then this [email protected]@ZIF-8 complex was anchored with MPEG2000-COOH to yield an MPEG2000[email protected]@ZIF-8 (PSCZ) composite. This composite was then utilized as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI, remarkably improved intracellular enzyme delivery. The PSCZ composite showed a significantly relieve ability of H2O2 induced ROS and prevented apoptosis in HEK293 cells. In vivo, this composite showed a protective effect in the cisplatin-induced AKI mouse model. In addition, PSCZ treatment mitigated renal dysfunction and histological injury, like tubulointerstitial infiltration. RNA sequencing results further confirmed the protective effect of PSCZ and the potential molecular mechanism was revealed. PSCZ treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and inflammatory infiltration of renal tubules. Moreover, PSCZ administration regulated renal injury via the p53 signaling pathway. These renoprotective effects of PSCZ treatment were more potent in CP-AKI mice than those of SOD or CAT alone. This dual-enzyme-embedded metal-organic framework was able to scavenge reactive oxygen species synergistically and effectively.
Conclusion: PSCZ can remarkably improve intracellular enzyme delivery, and it can be used as a stable tool with antioxidant properties for the integrated cascade-based treatment of AKI. The ZIF-8-based “armor plating” represents an effective means of shielding enzymes with improved therapeutic utility to guide the precision medicine-based treatment of AKI.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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