Purpose: Aminopeptidase N (APN/CD13) plays an important role in tumor neoangiogenic process and the development of metastases. Furthermore, it may serve as a potential target for cancer diagnosis and therapy. Previous studies have already shown that asparagine-glycinearginine (NGR) peptides specifically bind to APN/CD13. The aim of the study was to synthesize and investigate the APN/CD13 specificity of a novel 68
Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide–daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2). The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma) and CD13 negative HT-29 (human colon adenocarcinoma) cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions.
AbstractIn drug targeting NGR-peptides recognized by CD13 receptors on tumor neovasculature have got improved interest. Here we present the synthesis and structure analysis of novel thioether linked cyclic NGR-peptides. We found that chemo-stability (resistance against spontaneous decomposition forming isoAsp and Asp derivatives) strongly depends both on sample handling conditions and structural properties. Significant correlation was found between chemo-stability and structural measures: e.g. NH Gly …CO Asn-sc distances. Side chain orientation of Asn is the key determining factor, if turned away from HN Gly chemo-stability increases. Structure stabilizing factors (e.g. H-bond(s)) lower their internal dynamics and thus macromolecules become even more resistant against spontaneous decomposition. Effect of cyclic NGR-peptides on cell adhesion was examined on A2058 melanoma cell lines. It was found that some of them gradually increased the cell adhesion with long term characteristics indicating the time-dependent formation of integrin binding isoAsp derivatives, responsible for the adhesion inducing effect.
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