TY - JOUR
T1 - Nanoformulation of the superoxide dismutase mimic, MnTnBuOE-2-PyP5+, prevents its acute hypotensive response
AU - Schlichte, Sarah L.
AU - Romanova, Svetlana
AU - Katsurada, Kenichi
AU - Kosmacek, Elizabeth A.
AU - Bronich, Tatiana K.
AU - Patel, Kaushik P.
AU - Oberley-Deegan, Rebecca E.
AU - Zimmerman, Matthew C.
N1 - Funding Information:
This project was supported, in part, by the UNMC Center for Heart and Vascular Research (CHVR) , and by the National Institute of General Medical Sciences , 1U54GM115458 , which funds the Great Plains IDeA-CTR Network. This work was also supported by the National Institutes of Health grants R01DK114663 and P01HL62222 (to K.P. Patel), as well as R01CA178888 and SP20GM103480 (to R.E. Oberley-Deegan), and an endowed McIntyre Professorship to K.P. Patel. The content is solely the responsibility of the authors and does not necessarily represent the official views of CHVR or the NIH. EPR spectroscopy data was collected in the University of Nebraska's EPR Spectroscopy Core, which was initially established with support from a Center of Biomedical Research Excellence grant from the National Institute of General Medical Sciences of the National Institutes of Health ( P30GM103335 ) awarded to the University of Nebraska's Redox Biology Center. We also acknowledge the assistance of the Nanomaterials Core Facility of the Center for Biomedical Research Excellence, Nebraska Center for Nanomedicine supported by the Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30GM127200 .
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Blood pressure
KW - Mesoporous silica nanoparticle
KW - MnTnBuOE-2-PyP
KW - Renal sympathetic nerve activity
KW - SOD Mimic
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U2 - 10.1016/j.redox.2020.101610
DO - 10.1016/j.redox.2020.101610
M3 - Article
C2 - 32863236
AN - SCOPUS:85086832562
VL - 36
JO - Redox Biology
JF - Redox Biology
SN - 2213-2317
M1 - 101610
ER -