Nanoformulation of the Superoxide Dismutase Mimic, MnTnBuOE-2-PyP5+, Prevents its Acute Hypotensive Response

Authors

Sarah L. Schlichte, University of Nebraska Medical CenterFollow
Svetlana Romanova, University of Nebraska Medical CenterFollow
Kenichi Katsurada, University of Nebraska Medical Center
Elizabeth A. Kosmacek, University of Nebraska Medical CenterFollow
Tatiana K. Bronich, University of Nebraska Medical CenterFollow
Kaushik K. Patel, University of Nebraska Medical CenterFollow
Rebecca E. Oberley-Deegan, University of Nebraska Medical CenterFollow
Matthew C. Zimmerman, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Redox Biology

Publication Date

2020

Volume

36

Abstract

Scavenging superoxide (O₂^•-) via overexpression of superoxide dismutase (SOD) or administration of SOD mimics improves outcomes in multiple experimental models of human disease including cardiovascular disease, neurodegeneration, and cancer. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP⁵⁺ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials as a radioprotector for cancer patients; thus, providing hope for the use of SOD mimics in the clinical setting. However, BuOE transiently alters cardiovascular function including a significant and precipitous decrease in blood pressure. To limit BuOE's acute hypotensive action, we developed a mesoporous silica nanoparticle and lipid bilayer nanoformulation of BuOE (nanoBuOE) that allows for slow and sustained release of the drug. Herein, we tested the hypothesis that unlike native BuOE, nanoBuOE does not induce an acute hypotensive response, as the nanoformulation prevents BuOE from scavenging O₂^•- while the drug is still encapsulated in the formulation. We report that intact nanoBuOE does not effectively scavenge O₂^•-, whereas BuOE released from the nanoformulation does retain SOD-like activity. Further, in mice, native BuOE, but not nanoBuOE, rapidly, acutely, and significantly decreases blood pressure, as measured by radiotelemetry. To begin exploring the physiological mechanism by which native BuOE acutely decreases blood pressure, we recorded renal sympathetic nerve activity (RSNA) in rats. RSNA significantly decreased immediately following intravenous injection of BuOE, but not nanoBuOE. These data indicate that nanoformulation of BuOE, a SOD mimic currently in clinical trials in cancer patients, prevents BuOE's negative side effects on blood pressure homeostasis.

DOI Link

10.1016/j.redox.2020.101610

ISSN

2213-2317

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Schlichte, Sarah L.; Romanova, Svetlana; Katsurada, Kenichi; Kosmacek, Elizabeth A.; Bronich, Tatiana K.; Patel, Kaushik K.; Oberley-Deegan, Rebecca E.; and Zimmerman, Matthew C., "Nanoformulation of the Superoxide Dismutase Mimic, MnTnBuOE-2-PyP5+, Prevents its Acute Hypotensive Response" (2020). Journal Articles: Cellular & Integrative Physiology. 38.
https://digitalcommons.unmc.edu/com_cell_articles/38