Abstract
Tumor hypoxia induces angiogenesis, which is required for tumor cell survival. The aminopeptidase N receptor (APN/CD13) is an excellent marker of angiogenesis since it is overexpressed in angiogenic blood vessels and in tumor cells. Asparagine-glycine-arginine (NGR) peptide analogs bind selectively to the APN/CD13 recepto, therefore, they are important vector molecules in the development of a PET radiotracer which is capable of detecting APN-rich tumors. To investigate the effect of glycosylation and pegylation on in-vivo efficacy of an NGR-based radiotracer, two 68Ga-labeled radioglycopeptides were synthesized. A lactosamine derivative was applied to glycosylation of the NGR derivative and PEG4 moiety was used for pegylation. The receptor targeting potential and biodistribution of the radiopeptides were evaluated with in vivo PET imaging studies and ex vivo tissue distribution studies using B16-F10 melanoma tumor-bearing mice. According to these studies, all synthesized radiopeptides were capable of detecting APN expression in B16-F10 melanoma tumor. In addition, lower hepatic uptake, higher tumor-to background (T/M) ratio and prolonged circulation time were observed for the novel [68Ga]-10 radiotracer due to pegylation and glycosylation, resulting in more contrasting PET imaging. These in vivo PET imaging results correlated well with the ex vivo tissue distribution data.
Highlights
This article is an open access articleInitially, small tumors do not have their own vascular network; tumor growth can stop due to a lack of oxygen and nutrients
We have previously reported the synthesis and radiochemical investigation of a glycopeptide, 68 Ga-NODAGA-LacN-E[c(RGDfK)]2, which may be suitable for the detection of αv β3 integrin and galectin-3 expression in tumor endothelial and cancer cells by Positron emission tomography (PET) imaging [31]
We have successfully completed the synthesis and radiolabeling of two NGR-based glycopeptides (9 and 10) and DOTAGA-cKNGRE (11), which are suitable for the detection of APN-positive tumors by PET imaging
Summary
Small tumors do not have their own vascular network; tumor growth can stop due to a lack of oxygen and nutrients. Oxygen deficiency induces angiogenesis and new capillaries are formed from existing vessels to allow tumor cells to survive [1]. Since angiogenesis leads to tumor growth and malignant development, inhibiting of tumor neovascularization is a valuable approach to anticancer therapy. This distributed under the terms and conditions of the Creative Commons. APN/CD13 is a Zn2+ -dependent membrane-bound enzyme that degrades proteins and peptides with an N-terminal amino acid and is a regulator of malignancies, such as tumor cell invasion, differentiation, proliferation, apoptosis, and angiogenesis.
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