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Title: Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery

Abstract

Optical imaging strategies for improving delineation of glioblastoma (GBM) is highly desired for guiding surgeons to distinguish cancerous tissue from healthy and precious brain tissue. Fluorescence imaging (FLI) in the second near-infrared window (NIR-II) outperforms traditional NIR-I imaging with better tissue penetration, higher spatial and temporal resolution, and less auto fluorescence and scattering. Because of high expression in GBM and many other tumors, urokinase Plasminogen Activator Receptor (uPAR) is an attractive and well proven target for FLI. Herein we aim to combine the benefit of a NIR-II fluorophore with a high affinity uPAR targeting small peptide. A targeted NIR-II fluorescent probe was developed by conjugating an in-house synthesized NIR-II fluorophore, CH1055, and a uPAR targeting peptide, AE105. To characterize the in vivo distribution and targeting properties, a dynamic imaging was performed in orthotopic GBM bearing nude mice (n = 8). Additionally, fluorescence guided surgery of orthotopic GBM was performed in living animals. CH1055-4Glu-AE105 was easily synthesized with >75% yield and >98% HPLC evaluated purity. The retention time of the probe on analytical HPLC was 15.9 min and the product was verified by mass spectrometry. Dynamic imaging demonstrated that the uPAR targeting probe visualized orthotopic GBM through the intact skull withmore » a tumor-to-background ratio (TBR) of 2.7 peaking at 96 h. Further, the orthotopic GBM was successfully resected in small animals guided by the NIR-II FLI. By using a small uPAR targeting NIR-II probe, FLI allows us to specifically image and detect GBM. A real-time imaging setup further renders FLI guided tumor resection, and the probe developed in this work is a promising candidate for clinical translation.« less

Authors:
ORCiD logo [1];  [2];  [3];  [3];  [3];  [4];  [5];  [2]; ORCiD logo [3]
+ Show Author Affiliations
  1. Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, California, 94305-5344, United States, Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, 2200 Copenhagen N, Denmark
  2. Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, 2200 Copenhagen N, Denmark
  3. Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, California, 94305-5344, United States
  4. Finsen Laboratory, Rigshospitalet, 2200 Copenhagen N, Denmark, Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen N, Denmark
  5. Department of Plastic Surgery, Breast Surgery and Burns Treatment, Rigshospitalet and University of Copenhagen, 2100 Copenhagen Ø, Denmark
Publication Date:
Research Org.:
Stanford Univ., CA (United States); Univ. of Copenhagen (Denmark)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1493382
Alternate Identifier(s):
OSTI ID: 1508750
Grant/Contract Number:  
SC0008397
Resource Type:
Published Article
Journal Name:
Bioconjugate Chemistry
Additional Journal Information:
Journal Name: Bioconjugate Chemistry Journal Volume: 29 Journal Issue: 11; Journal ID: ISSN 1043-1802
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kurbegovic, Sorel, Juhl, Karina, Chen, Hao, Qu, Chunrong, Ding, Bingbing, Leth, Julie Maja, Drzewiecki, Krzysztof Tadeusz, Kjaer, Andreas, and Cheng, Zhen. Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery. United States: N. p., 2018. Web. doi:10.1021/acs.bioconjchem.8b00669.
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Kurbegovic, Sorel, Juhl, Karina, Chen, Hao, Qu, Chunrong, Ding, Bingbing, Leth, Julie Maja, Drzewiecki, Krzysztof Tadeusz, Kjaer, Andreas, & Cheng, Zhen. Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery. United States. https://doi.org/10.1021/acs.bioconjchem.8b00669
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Kurbegovic, Sorel, Juhl, Karina, Chen, Hao, Qu, Chunrong, Ding, Bingbing, Leth, Julie Maja, Drzewiecki, Krzysztof Tadeusz, Kjaer, Andreas, and Cheng, Zhen. Mon . "Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery". United States. https://doi.org/10.1021/acs.bioconjchem.8b00669.
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@article{osti_1493382,
title = {Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery},
author = {Kurbegovic, Sorel and Juhl, Karina and Chen, Hao and Qu, Chunrong and Ding, Bingbing and Leth, Julie Maja and Drzewiecki, Krzysztof Tadeusz and Kjaer, Andreas and Cheng, Zhen},
abstractNote = {Optical imaging strategies for improving delineation of glioblastoma (GBM) is highly desired for guiding surgeons to distinguish cancerous tissue from healthy and precious brain tissue. Fluorescence imaging (FLI) in the second near-infrared window (NIR-II) outperforms traditional NIR-I imaging with better tissue penetration, higher spatial and temporal resolution, and less auto fluorescence and scattering. Because of high expression in GBM and many other tumors, urokinase Plasminogen Activator Receptor (uPAR) is an attractive and well proven target for FLI. Herein we aim to combine the benefit of a NIR-II fluorophore with a high affinity uPAR targeting small peptide. A targeted NIR-II fluorescent probe was developed by conjugating an in-house synthesized NIR-II fluorophore, CH1055, and a uPAR targeting peptide, AE105. To characterize the in vivo distribution and targeting properties, a dynamic imaging was performed in orthotopic GBM bearing nude mice (n = 8). Additionally, fluorescence guided surgery of orthotopic GBM was performed in living animals. CH1055-4Glu-AE105 was easily synthesized with >75% yield and >98% HPLC evaluated purity. The retention time of the probe on analytical HPLC was 15.9 min and the product was verified by mass spectrometry. Dynamic imaging demonstrated that the uPAR targeting probe visualized orthotopic GBM through the intact skull with a tumor-to-background ratio (TBR) of 2.7 peaking at 96 h. Further, the orthotopic GBM was successfully resected in small animals guided by the NIR-II FLI. By using a small uPAR targeting NIR-II probe, FLI allows us to specifically image and detect GBM. A real-time imaging setup further renders FLI guided tumor resection, and the probe developed in this work is a promising candidate for clinical translation.},
doi = {10.1021/acs.bioconjchem.8b00669},
journal = {Bioconjugate Chemistry},
number = 11,
volume = 29,
place = {United States},
year = {Mon Oct 08 00:00:00 EDT 2018},
month = {Mon Oct 08 00:00:00 EDT 2018}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acs.bioconjchem.8b00669
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Cited by: 42 works
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Figures / Tables:

Figure 1. Figure 1.: (a) Peptide sequence and schematic molecular structure of CH1055-4Glu-AE105; (b) analytical HPLC of purified probe; (c) MALDI-TOF mass spectrum of CH1055-4Glu-AE105; (d) affinity to the uPAR receptor for the NIR-II labeled peptide (CH1055-4GluAE105) and the nonlabeled peptide (AE105); (e) absorbance and fluorescent emission of CH1055, demonstrating an absorbancemore » peak at ∼750 nm and an emission peak at ∼1055 nm. The fluorescent emission spectrum was obtained with an 808 nm excitation laser.« less
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