Evaluation of 188Re-labeled NGR–VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts

Abstract

Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine-glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of (188)Re-NGR-VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

In vivo assessment of aminopeptidase N (APN/CD13) specificity of different 68Ga-labelled NGR derivatives using PET/MRI imaging

“…The radiolabelling of NGR probes by diagnostic and therapeutic radionuclides (e.g. : 64 Cu (Li et al, 2014), 68 Ga (Máté et al, 2015;Satpati et al, 2017), 99m Tc (Vats et al, 2017), 177 Lu (Vats et al, 2018), 188 Re (Ma et al, 2016)) provides an opportunity to monitor the in vivo biodistribution and tumor-targeting properties of the novel NGR derivatives, furthermore, give the possibility to follow the efficacy of anti-cancer therapies using in vivo molecular imaging. In addition, the detection of the APN/CD13 molecule is particularly important because it has been observed that it is not only a diagnostic but also a prognostic marker, that may predict the mortality and overall survival (Kessler et al, 2018;Schreiber et al, 2018).…”

The uptake exploration of 68Ga-labeled NGR in well-differentiated hepatocellular carcinoma xenografts: Indication for the new clinical translational of a tracer based on NGR

“…The development of radio-labeled peptide probes, such as RGD and NGR, for diagnostic and therapeutic applications, has rapidly expanded in the last decades (34)(35)(36)(37). On the aspect of clinical practice, the safety and the applicability of these probes have been well established in lung cancer (38)(39)(40), brain metastases (41), breast cancer (42) and rheumatoid arthritis (43).…”

Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status

“…188 Re has similar chemical characteristics as 99m Tc but emits an electron in addition to gamma lines that are suitable for SPECT—making the isotope suitable for radionuclide therapy. They demonstrated a favourable tumour to background ratio in HT-1080 tumour xenografts using SPECT, and more importantly showed that when applied in therapeutic concentrations [ 188 Re]Re-NGR-VEGI showed excellent tumour inhibition effect with no observable toxicity [ 157 ]. Zhao et al combined RGD with Evans blue and subsequently labelled this peptide analogue with 177 Lu, another therapeutic isotope.…”