Real-time near-infrared fluorescence imaging using cRGD-ZW800-1 for intraoperative visualization of multiple cancer types
2017
// Henricus J.M. Handgraaf 1, * , Martin C. Boonstra 1, * , Hendrica A.J.M. Prevoo 1 , Joeri Kuil 2 , Mark W. Bordo 3 , Leonora S.F. Boogerd 1 , Babs G. Sibinga Mulder 1 , Cornelis F.M. Sier 1 , Maaike L. Vinkenburg-van Slooten 1 , A. Rob P.M. Valentijn 2 , Jacobus Burggraaf 4, 5 , Cornelis J.H. van de Velde 1 , John V. Frangioni 3, 6, 7 , Alexander L. Vahrmeijer 1 1 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands 2 Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands 3 Curadel, LLC, Marlborough, MA, U.S.A 4 Centre for Human Drug Research, Leiden, The Netherlands 5 Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands 6 Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, U.S.A 7 Department 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: a.l.vahrmeijer@lumc.nl 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 α V β 3 . 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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
41
References
36
Citations
NaN
KQI