64Cu-1,4,7-Triazacyclononane-1,4,7-triacetic acid- p-isothiocyanatobenzyl-bevacizumab-IRDye 800CW

Excerpt

The vascular endothelial growth factor (VEGF) family is composed of five VEGF glycoproteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E) and consists of at least six isoforms of various numbers of amino acids (121, 145, 165, 183, 189, and 206 amino acids) produced through alternative splicing (1). VEGF-A is composed of VEGF₁₂₁, VEGF₁₆₅, and VEGF₁₈₉ isoforms, which are secreted by most cell types and are active as homodimers linked by disulfide bonds. VEGF₁₂₁ does not bind to heparin like other VEGF polypeptides do (2). VEGF is a potent angiogenic factor that induces proliferation, sprouting, migration, and tube formation of endothelial cells. There are three high-affinity tyrosine kinase VEGF receptors (VEGFR-1, Flt-1; VEGFR-2, KDR/Flt-1; and VEGFR-3, Flt-4) on endothelial cells. Several types of non-endothelial cells, such as hematopoietic stem cells, melanoma cells, monocytes, osteoblasts, and pancreatic β cells, also express VEGFRs (1).

VEGF is overexpressed in various tumor cells and tumor-associated endothelial cells (3). Among the at least seven isoforms of VEGF-A, VEGF₁₂₁ is freely soluble while all VEGF₁₈₉ is bound to the cell membrane or extracellular matrix (ECM). VEGF₁₆₅ exhibits an intermediary behavior (i.e. partly diffusible and partly bound). Inhibition of VEGFR function has been shown to inhibit pathological angiogenesis as well as tumor growth and metastasis (4, 5). Radiolabeled VEGF has been developed as a single-photon emission computed tomography tracer for imaging solid tumors and angiogenesis in humans (6-8). However, several studies have shown that cancer treatments (photodynamic therapy, radiotherapy, and chemotherapy) can lead to increased tumor VEGF expression and subsequently to more aggressive disease (9, 10). Therefore, it is important to measure VEGF levels in the tumors to design better anticancer treatment protocols. Bevacizumab (Bev) is a humanized antibody against VEGF-A (11) that binds to all VEGF-A isoforms, and it is approved for clinical use in metastatic colon carcinoma and non-small cell lung cancer (12). VEGFR-2 has been shown to mediate most of the VEGF-A activation in tumor endothelial cells (13, 14). Zhang et al. (15) prepared ⁶⁴Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid-p-isothiocyanatobenzyl-bevacizumab-IRDye 800CW (⁶⁴Cu-NOTA-Bev-800CW) for positron emission tomography (PET) and near-infrared fluorescence (NIR) multimodal imaging of VEGF expression in nude mice bearing U87MG human glioblastoma xenografts. U87MG cells express all three isoforms of VEGF-A (VEGF_121, VEGF_165, and VEGF₁₈₉).