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Structure-Activity Relationship of Nerve-Highlighting Fluorophores

Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate b...

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Autores principales: Gibbs, Summer L., Xie, Yang, Goodwill, Haley L., Nasr, Khaled A., Ashitate, Yoshitomo, Madigan, Victoria J., Siclovan, Tiberiu M., Zavodszky, Maria, Tan Hehir, Cristina A., Frangioni, John V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767781/
https://www.ncbi.nlm.nih.gov/pubmed/24039960
http://dx.doi.org/10.1371/journal.pone.0073493
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author Gibbs, Summer L.
Xie, Yang
Goodwill, Haley L.
Nasr, Khaled A.
Ashitate, Yoshitomo
Madigan, Victoria J.
Siclovan, Tiberiu M.
Zavodszky, Maria
Tan Hehir, Cristina A.
Frangioni, John V.
author_facet Gibbs, Summer L.
Xie, Yang
Goodwill, Haley L.
Nasr, Khaled A.
Ashitate, Yoshitomo
Madigan, Victoria J.
Siclovan, Tiberiu M.
Zavodszky, Maria
Tan Hehir, Cristina A.
Frangioni, John V.
author_sort Gibbs, Summer L.
collection PubMed
description Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.
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spelling pubmed-37677812013-09-13 Structure-Activity Relationship of Nerve-Highlighting Fluorophores Gibbs, Summer L. Xie, Yang Goodwill, Haley L. Nasr, Khaled A. Ashitate, Yoshitomo Madigan, Victoria J. Siclovan, Tiberiu M. Zavodszky, Maria Tan Hehir, Cristina A. Frangioni, John V. PLoS One Research Article Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability. Public Library of Science 2013-09-09 /pmc/articles/PMC3767781/ /pubmed/24039960 http://dx.doi.org/10.1371/journal.pone.0073493 Text en © 2013 Gibbs et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gibbs, Summer L.
Xie, Yang
Goodwill, Haley L.
Nasr, Khaled A.
Ashitate, Yoshitomo
Madigan, Victoria J.
Siclovan, Tiberiu M.
Zavodszky, Maria
Tan Hehir, Cristina A.
Frangioni, John V.
Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title_full Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title_fullStr Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title_full_unstemmed Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title_short Structure-Activity Relationship of Nerve-Highlighting Fluorophores
title_sort structure-activity relationship of nerve-highlighting fluorophores
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767781/
https://www.ncbi.nlm.nih.gov/pubmed/24039960
http://dx.doi.org/10.1371/journal.pone.0073493
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