Theranostics 2021; 11(15):7159-7174. doi:10.7150/thno.49787 This issue Cite

Research Paper

IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts

Sorel Kurbegovic1, Karina Juhl1, Kasper Kildegaard Sørensen2, Julie Leth3, Gro Linno Willemoe4, Anders Christensen1,5, Yvonne Adams6, Anja Ramstedt Jensen6, Christian von Buchwald5, Jane Skjøth-Rasmussen7, Michael Ploug3, Knud J. Jensen2, Andreas Kjaer1✉

1. Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen.
2. Department of Chemistry, University of Copenhagen, Denmark.
3. Finsen Laboratory and Biotech Research and Innovation Centre (BRIC), Rigshospitalet and University of Copenhagen, Denmark.
4. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Denmark.
5. Department of Otorhinolaryngology, Head and neck surgery & Audiology, Rigshospitalet, Copenhagen University Hospital, Denmark.
6. Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
7. Department of Neurosurgery, Neuroscience Center, Rigshospitalet, Copenhagen University Hospital, Denmark.

Citation:
Kurbegovic S, Juhl K, Sørensen KK, Leth J, Willemoe GL, Christensen A, Adams Y, Jensen AR, von Buchwald C, Skjøth-Rasmussen J, Ploug M, Jensen KJ, Kjaer A. IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts. Theranostics 2021; 11(15):7159-7174. doi:10.7150/thno.49787. https://www.thno.org/v11p7159.htm
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Abstract

Graphic abstract

Glioblastoma (GBM) is a devastating cancer with basically no curative treatment. Even with aggressive treatment, the median survival is disappointing 14 months. Surgery remains the key treatment and the postoperative survival is determined by the extent of resection. Unfortunately, the invasive growth with irregular infiltrating margins complicates an optimal surgical resection. Precise intraoperative tumor visualization is therefore highly needed and molecular targeted near-infrared (NIR) fluorescence imaging potentially constitutes such a tool. The urokinase-type Plasminogen Activator Receptor (uPAR) is expressed in most solid cancers primarily at the invading front and the adjacent activated peritumoral stroma making it an attractive target for targeted fluorescence imaging. The purpose of this study was to develop and evaluate a new uPAR-targeted optical probe, IRDye800CW-AE344, for fluorescence guided surgery (FGS).

Methods: In the present study we characterized the fluorescent probe with regard to binding affinity, optical properties, and plasma stability. Further, in vivo imaging characterization was performed in nude mice with orthotopic human patient derived glioblastoma xenografts, and we performed head-to-head comparison within FGS between our probe and the traditional procedure using 5-ALA. Finally, the blood-brain barrier (BBB) penetration was characterized in a 3D BBB spheroid model.

Results: The probe effectively visualized GBM in vivo with a tumor-to-background ratio (TBR) above 4.5 between 1 to 12 h post injection and could be used for FGS of orthotopic human glioblastoma xenografts in mice where it was superior to 5-ALA. The probe showed a favorable safety profile with no evidence of any acute toxicity. Finally, the 3D BBB model showed uptake of the probe into the spheroids indicating that the probe crosses the BBB.

Conclusion: IRDye800CW-AE344 is a promising uPAR-targeted optical probe for FGS and a candidate for translation into human use.

Keywords: optical imaging, fluorescence-guided surgery, glioblastoma, uPAR, molecular targeted imaging


Citation styles

APA
Kurbegovic, S., Juhl, K., Sørensen, K.K., Leth, J., Willemoe, G.L., Christensen, A., Adams, Y., Jensen, A.R., von Buchwald, C., Skjøth-Rasmussen, J., Ploug, M., Jensen, K.J., Kjaer, A. (2021). IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts. Theranostics, 11(15), 7159-7174. https://doi.org/10.7150/thno.49787.

ACS
Kurbegovic, S.; Juhl, K.; Sørensen, K.K.; Leth, J.; Willemoe, G.L.; Christensen, A.; Adams, Y.; Jensen, A.R.; von Buchwald, C.; Skjøth-Rasmussen, J.; Ploug, M.; Jensen, K.J.; Kjaer, A. IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts. Theranostics 2021, 11 (15), 7159-7174. DOI: 10.7150/thno.49787.

NLM
Kurbegovic S, Juhl K, Sørensen KK, Leth J, Willemoe GL, Christensen A, Adams Y, Jensen AR, von Buchwald C, Skjøth-Rasmussen J, Ploug M, Jensen KJ, Kjaer A. IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts. Theranostics 2021; 11(15):7159-7174. doi:10.7150/thno.49787. https://www.thno.org/v11p7159.htm

CSE
Kurbegovic S, Juhl K, Sørensen KK, Leth J, Willemoe GL, Christensen A, Adams Y, Jensen AR, von Buchwald C, Skjøth-Rasmussen J, Ploug M, Jensen KJ, Kjaer A. 2021. IRDye800CW labeled uPAR-targeting peptide for fluorescence-guided glioblastoma surgery: Preclinical studies in orthotopic xenografts. Theranostics. 11(15):7159-7174.

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