TY - JOUR

T1 - Molecular Targeted NIR-II Probe for Image-Guided Brain Tumor Surgery

AU - Kurbegovic, Sorel

AU - Juhl, Karina

AU - Chen, Hao

AU - Qu, Chunrong

AU - Ding, Bingbing

AU - Leth, Julie Maja

AU - Drzewiecki, Krzysztof Tadeusz

AU - Kjaer, Andreas

AU - Cheng, Zhen

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1021/acs.bioconjchem.8b00669

DO - 10.1021/acs.bioconjchem.8b00669

M3 - Journal article

C2 - 30296054

AN - SCOPUS:85055722280

VL - 29

SP - 3833

EP - 3840

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 11

ER -