Oncotarget

Research Papers:

Real-time near-infrared fluorescence imaging using cRGD-ZW800-1 for intraoperative visualization of multiple cancer types

Henricus J.M. Handgraaf, Martin C. Boonstra, Hendrica A.J.M. Prevoo, Joeri Kuil, Mark W. Bordo, Leonora S.F. Boogerd, Babs G. Sibinga Mulder, Cornelis F.M. Sier, Maaike L. Vinkenburg-van Slooten, A. Rob P.M. Valentijn, Jacobus Burggraaf, Cornelis J.H. van de Velde, John V. Frangioni and Alexander L. Vahrmeijer _

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Oncotarget. 2017; 8:21054-21066. https://doi.org/10.18632/oncotarget.15486

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Abstract

Henricus J.M. Handgraaf1,*, Martin C. Boonstra1,*, Hendrica A.J.M. Prevoo1, Joeri Kuil2, Mark W. Bordo3, Leonora S.F. Boogerd1, Babs G. Sibinga Mulder1, Cornelis F.M. Sier1, Maaike L. Vinkenburg-van Slooten1, A. Rob P.M. Valentijn2, Jacobus Burggraaf4,5, Cornelis J.H. van de Velde1, John V. Frangioni3,6,7, Alexander L. Vahrmeijer1

1Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

2Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

3Curadel, LLC, Marlborough, MA, U.S.A

4Centre for Human Drug Research, Leiden, The Netherlands

5Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands

6Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, U.S.A

7Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, U.S.A

*These authors contributed equally and share first authorship

Correspondence to:

Alexander L. Vahrmeijer, email: [email protected]

Keywords: integrins, RGD, fluorescence-guided surgery, preclinical validation, in vivo diagnosis

Received: December 15, 2016     Accepted: February 07, 2017     Published: February 18, 2017

ABSTRACT

Incomplete resections and damage to critical structures increase morbidity and mortality of patients with cancer. Targeted intraoperative fluorescence imaging aids surgeons by providing real-time visualization of tumors and vital structures. This study evaluated the tumor-targeted zwitterionic near-infrared fluorescent peptide cRGD-ZW800-1 as tracer for intraoperative imaging of multiple cancer types. cRGD-ZW800-1 was validated in vitro on glioblastoma (U-87 MG) and colorectal (HT-29) cell lines. Subsequently, the tracer was tested in orthotopic mouse models with HT-29, breast (MCF-7), pancreatic (BxPC-3), and oral (OSC-19) tumors. Dose-ranging studies, including doses of 0.25, 1.0, 10, and 30 nmol, in xenograft tumor models suggest an optimal dose of 10 nmol, corresponding to a human equivalent dose of 63 μg/kg, and an optimal imaging window between 2 and 24 h post-injection. The mean half-life of cRGD-ZW800-1 in blood was 25 min. Biodistribution at 4 h showed the highest fluorescence signals in tumors and kidneys. In vitro and in vivo competition experiments showed significantly lower fluorescence signals when U-87 MG cells (minus 36%, p = 0.02) or HT-29 tumor bearing mice (TBR at 4 h 3.2 ± 0.5 vs 1.8 ± 0.4, p = 0.03) were simultaneously treated with unlabeled cRGD. cRGD-ZW800-1 visualized in vivo all colorectal, breast, pancreatic, and oral tumor xenografts in mice. Screening for off-target interactions, cRGD-ZW800-1 showed only inhibition of COX-2, likely due to binding of cRGD-ZW800-1 to integrin αVβ3. Due to its recognition of various integrins, which are expressed on malignant and neoangiogenic cells, it is expected that cRGD-ZW800-1 will provide a sensitive and generic tool to visualize cancer during surgery.


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