TY - JOUR
T1 - Fluorescence Imaging of Peripheral Nerves by a Nav1.7-Targeted Inhibitor Cystine Knot Peptide
AU - Gonzales, Junior
AU - Demetrio De Souza Franca, Paula
AU - Jiang, Yan
AU - Pirovano, Giacomo
AU - Kossatz, Susanne
AU - Guru, Navjot
AU - Yarilin, Dimitry
AU - Agwa, Akello J.
AU - Schroeder, Christina I.
AU - Patel, Snehal G.
AU - Ganly, Ian
AU - King, Glenn F.
AU - Reiner, Thomas
N1 - Funding Information:
This work was supported by the National Institutes of Health (grants R01 CA204441, P30 CA008748, R43 CA228815, and K99 CA218875), the Australian National Health and Medical Research Council (Project Grant APP1080405, Program Grant APP1072113 and Principal Research Fellowship APP1044414), the Australian Research Council (Future Fellowship FT160100055) and a University of Queensland International Postgraduate Research Scholarship. The authors thank the Tow Foundation and Memorial Sloan Kettering Cancer Center’s Center for Molecular Imaging & Nanotechnology (CMINT), the Imaging and Radiation Sciences Program and the MSK Molecularly Targeted Intraoperative Imaging Fund. The authors thank the Small Animal Imaging Core (V. Longo, P. Zanzonico), the Radiochemistry and Molecular Imaging Probes Core (S. Lyashchenko, K. Staton), and the Molecular Cytology Core (D. Yarilin) at Memorial Sloan Kettering Cancer Center for support. The authors also thank Jack Moore from the University of Alberta Proteomics and Mass Spectrometry Facility for help with tryptic digests, and Dr. Jason S. Lewis and Dr. Sai Sharma from Memorial Sloan Kettering Cancer Center for helpful discussions.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2019/11/20
Y1 - 2019/11/20
N2 - Twenty million Americans suffer from peripheral nerve injury caused by trauma and medical disorders, resulting in a broad spectrum of potentially debilitating side effects. In one out of four cases, patients identify surgery as the root cause of their nerve injury. Particularly during tumor resections or after traumatic injuries, tissue distortion and poor visibility can challenge a surgeon's ability to precisely locate and preserve peripheral nerves. Intuitively, surgical outcomes would improve tremendously if nerves could be highlighted using an exogeneous contrast agent. In clinical practice, however, the current standard of care - visual examination and palpation - remains unchanged. To address this unmet clinical need, we explored the expression of voltage-gated sodium channel Nav1.7 as an intraoperative marker for the peripheral nervous system. We show that expression of Nav1.7 is high in peripheral nerves harvested from both human and mouse tissue. We further show that modification of a Nav1.7-selective peptide, Hsp1a, can serve as a targeted vector for delivering a fluorescent sensor to the peripheral nervous system. Ex vivo, we observe a high signal-to-noise ratio for fluorescently labeled Hsp1a in both histologically prepared and fresh tissue. Using a surgical fluorescent microscope, we show in a simulated clinical scenario that the identification of mouse sciatic nerves is possible, suggesting that fluorescently labeled Hsp1a tracers could be used to discriminate nerves from their surrounding tissues in a routine clinical setting.
AB - Twenty million Americans suffer from peripheral nerve injury caused by trauma and medical disorders, resulting in a broad spectrum of potentially debilitating side effects. In one out of four cases, patients identify surgery as the root cause of their nerve injury. Particularly during tumor resections or after traumatic injuries, tissue distortion and poor visibility can challenge a surgeon's ability to precisely locate and preserve peripheral nerves. Intuitively, surgical outcomes would improve tremendously if nerves could be highlighted using an exogeneous contrast agent. In clinical practice, however, the current standard of care - visual examination and palpation - remains unchanged. To address this unmet clinical need, we explored the expression of voltage-gated sodium channel Nav1.7 as an intraoperative marker for the peripheral nervous system. We show that expression of Nav1.7 is high in peripheral nerves harvested from both human and mouse tissue. We further show that modification of a Nav1.7-selective peptide, Hsp1a, can serve as a targeted vector for delivering a fluorescent sensor to the peripheral nervous system. Ex vivo, we observe a high signal-to-noise ratio for fluorescently labeled Hsp1a in both histologically prepared and fresh tissue. Using a surgical fluorescent microscope, we show in a simulated clinical scenario that the identification of mouse sciatic nerves is possible, suggesting that fluorescently labeled Hsp1a tracers could be used to discriminate nerves from their surrounding tissues in a routine clinical setting.
UR - http://www.scopus.com/inward/record.url?scp=85075648249&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.9b00612
DO - 10.1021/acs.bioconjchem.9b00612
M3 - Article
C2 - 31647222
AN - SCOPUS:85075648249
SN - 1043-1802
VL - 30
SP - 2879
EP - 2888
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 11
ER -