Molecular imaging of glioblastoma multiforme using anti-insulin-like growth factor-binding protein-7 single-domain antibodies

Abstract

Background:Insulin-like growth factor-binding protein 7 (IGFBP7) is an abundant, selective and accessible biomarker of glioblastoma multiforme (GBM) tumour vessels. In this study, an anti-IGFBP7 single-domain antibody (sdAb) was developed to target GBM vessels for molecular imaging applications.Methods:Human GBM was modelled in mice by intracranial implantation of U87MG.EGFRvIII cells. An anti-IGFBP7 sdAb, isolated from an immune llama library by panning, was assessed in vitro for its binding affinity using surface plasmon resonance and by ex vivo immunobinding on mouse and human GBM tissue. Tumour targeting by Cy5.5-labelled anti-IGFBP7 sdAb as well as by anti-IGFBP7 sdAb conjugated to PEGylated Fe3O4 nanoparticles (NPs)-Cy5.5 were assessed in U87MG.EGFRvIII tumour-bearing mice in vivo using optical imaging and in brain sections using fluorescent microscopy.Results:Surface plasmon resonance analyses revealed a medium affinity (KD=40–50 n) binding of the anti-IGFBP7 sdAb to the purified antigen. The anti-IGFBP7 sdAb also selectively bound to both mouse and human GBM vessels, but not normal brain vessels in tissue sections. In vivo, intravenously injected anti-IGFBP7 sdAb-Cy5.5 bound to GBM vessels creating high imaging signal in the intracranial tumour. Similarly, the anti-IGFBP7 sdAb-functionalised PEGylated Fe3O4 NP-Cy5.5 demonstrated enhanced tumour signal compared with non-targeted NPs. Fluorescent microscopy confirmed the presence of anti-IGFBP7 sdAb and anti-IGFBP7 sdAb-PEGylated Fe3O4 NPs selectively in GBM vessels.Conclusions:Anti-IGFBP7 sdAbs are novel GBM vessel-targeting moieties suitable for molecular imaging.

IGFBP7 functions as a potential lymphangiogenesis inducer in non-small cell lung carcinoma

“…Hypomethylation of IGFBP7 is likely to characterize an immature and a more malignant subtype of the disease (33). In glioblastoma, developed anti-IGFBP7-iron oxide single domain antibody-targeted MRI contrast agent selectively binds to abnormal vessels (34), IGFBP7 antibody are novel glioblastoma vessel-targeting moieties suitable for molecular imaging (35), the retinal phenotype appears to be mediated by a role in the vascular endothelium, where IGFBP7 is highly expressed (36). In lung cancer patients, high serum levels of IGFBP7 is correlated with positive nodal status (P= 0.008), thus is not beneficial for recurrence-free survival (37), in vitro IGFBP7 is only reported during cancer progression and metastasis formation (38).…”

Engaging neuroscience to advance translational research in brain barrier biology

“…In addition, the recent introduction of optogenetic approaches 154 will allow investigators to examine discrete neuronal signaling events in the context of the NVU, providing a degree of in vivo analytical power previously achievable only using in vivo systems. Since brain vasculature is functionally implicated in many brain diseases (Table 1), molecular changes in the NVU could be exploited as image-able biomarkers for early diagnosis or monitoring of the disease using targeted molecular imaging agents 155 ; the added advantage of such biomarkers is their accessibility from the systemic circulation.…”

Multifunctional nanoparticles for brain tumor imaging and therapy

“…Optical imaging can aid in the intraoperative resection of brain tumors [159], and nanoparticle-based imaging probes with absorption and fluorescence properties have been developed with such capabilities. Quantum dots with intrinsic fluorescent properties allow for cancer targeting and imaging [66].…”