Abstract
Vascular endothelial growth factor receptor (VEGFR) is a critical factor in tumor angiogenesis and has been considered a potential target for receptor-mediated radionuclide imaging and therapy. In this study, we identified two peptides (QKRKRKKSRKKH and RKRKRKKSRYIVLS) derived from VEGF125-136 that displayed high binding affinities to VEGFR and strong inhibition of A549 cell growth. 99mTc- and 188Re-labeled peptides displayed high labeling efficiency and favorable stability in saline and human plasma. At the cellular level, the radiolabeled peptides could bind with A549 cells and be internalized via the VEGFR-1-mediated pathway. 99mTc/188Re-labeled peptide was significantly accumulated at xenograft tumors, as observed with single-photon emission computed tomography (SPECT) planar imaging. Moreover, 188Re-labeled peptides significantly inhibited tumor growth, prolonged the survival time of the tumor-bearing nude mice and resulted in much more necrotic regions and apoptotic cells in the A549 xenograft tumors. These results demonstrated that these two peptides as candidate drugs for radionuclide imaging and tumor therapy.
Highlights
Molecular imaging enables the detection and visualization of cancer-related biomarkers in tumors[1]
In vivo evaluation indicated that the peptide was a highly effective anti-angiogenesis agent that competed with vascular endothelial growth factor (VEGF) and suppressed ischemic retinal neovascularization as effectively as soluble Vascular endothelial growth factor receptor (VEGFR)-126
The inhibitory rates of the 13 peptides are shown in Fig. 1C, QKRKRKKSRKKH and RKRKRKKSRYIVLS displayed low IC50 values (79.75 ± 7.03 and 185.24 ± 14.18 nmol/L, respectively) as well as high inhibitory rates (40% and 70%, respectively), which indicates that these compounds were the optimal peptides after serial screening
Summary
Molecular imaging enables the detection and visualization of cancer-related biomarkers in tumors[1]. Molecular probes or tumor-targeted drugs could be labeled with different types of imaging agents for tumor imaging and therapy. Compared with normal cell types, VEGFRs are more highly expressed in tumor cells and in newly formed vascular endothelial cells[11, 12], which suggests that VEGF analogues are potential targeting drugs for receptor-mediated imaging[13, 14]. With the aim to improve target capability for tumor theranostics, we optimized VEGF125-136 via bioinformatics prediction and in vitro cell experimentation and obtained two peptides (QKRKRKKSRKKH and RKRKRKKSRYIVLS) with higher affinity to VRGFR than VEGF125-13628. These two peptides were labeled with 99mTc and 188Re, and in vitro and in vivo experiments were performed to evaluate their application for tumor imaging and therapeutic effect on A549 tumor-bearing nude mice; the underlying mechanism was preliminarily explored
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