Bevacizumab and near infrared probe conjugated iron oxide nanoparticles for vascular endothelial growth factor targeted MR and optical imaging

Abstract

Vascular endothelial growth factor (VEGF) plays a pivotal role in the cascade of development and progression of cancers. Targeting this cancer hallmark is a logical strategy for imaging based cancer detection and monitoring the anti-angiogenesis treatment. Using Bevacizumab (Avastin®), which is a recombinant humanized monoclonal antibody directly against VEGF and an angiogenesis inhibitor, as a targeting ligand, a multimodal VEGF targeted molecular imaging probe was developed by conjugating near infrared dye (NIR830) labeled bevacizumab to magnetic iron oxide nanoparticles (IONP) for optical and magnetic resonance (MR) imaging of cancers over-expressing VEGF. The targeting effect of NIR830-bevacizumab-IONPs on VEGF over-expressing cells was investigated by receptor mediated cell uptake experiments and a blocking assay using VEGF over-expressing 4T1 breast cancer cells. Systemic administration of VEGF-targeted NIR830-bevacizumab-IONPs into mice bearing 4T1 breast tumors resulted in higher accumulation of targeting IONPs in tumors compared to non-targeted IONPs. Quantitative analysis of T2-weighted MRI at 48 h post-injection revealed that the averaged percentage of signal intensity change in tumors treated with NIR830-bevacizumab-IONPs was 52.4 ± 11.0% compared to 26.9 ± 12.4% in controls treated with non-targeted IONPs. The results demonstrated the feasibility and efficacy of NIR830-bevacizumab-IONPs as a VEGF targeting dual-modality molecular imaging probe that can be potentially used for imaging of cancers with VEGF over-expression and delivery of bevacizumab for imaging guided anti-cancer treatment.

Tailoring Iron Oxide Nanoparticles for Efficient Cellular Internalization and Endosomal Escape

“…The most common antibodies for EGFR targeting include cetuximab [ 190 ], nimotuzumab [ 191 ], and single-chain antibody fragments (ScFv) [ 192 ]. In the case of VEGFR targeting, the preferred antibodies include bevacizumab [ 193 ] and anti-VEGF monoclonal antibodies [ 194 ]. The human epidermal receptor 2 (HER-2), a member of the EGFR family, has also been targeted with ION modified with a number of antibodies, including trastuzumab [ 195 ] and the anti-HER2 affibody [ 196 ].…”

A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis

“…Simultaneous optical and MR imaging of cancers was recently investigated by labeling recombinant humanized monoclonal antibodies or high-affinity small peptides against tumor receptors, which serve as targeting ligands, with near infrared dyes, and conjugating them to MNPs for simultaneous optical and MR imaging of cancers (Lin et al, 2018 ). Additionally, peptide-modified gadolinium oxide nanoprobes containing fluorescein for targeted MR/optical dual-modality imaging of various cancers have been engineered (Cui et al, 2017 ).…”

Iron Metabolism in Cancer

“…FTH overexpression also leads to a suppression of EMT, which suggests that labile iron is beneficial for tumor migration [111]. However, some studies indicate that iron may inhibit vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, tube formation, and sprouting [112]. Moreover, iron deficiency significantly promotes VEGF expression by stabilizing hypoxia-inducible factor-1α (HIF-1α) [113].…”