Abstract
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.
Highlights
Most of the currently used anticancer drugs have several shortcomings including poor bioavailability or lack of selectivity, which can result in serious side effects even at therapeutic doses
The extremely labile cyclic peptides produce isoaspartyl derivatives, which may be useful in a dual targeting approach in which the attached drugs are delivered to both CD13 receptor and the RGD-binding integrins
Six new cyclic NGR peptide–daunomycin conjugates were prepared with different structure in terms of conjugation sites and applied linkage in the cycle
Summary
Most of the currently used anticancer drugs have several shortcomings including poor bioavailability or lack of selectivity, which can result in serious side effects even at therapeutic doses. To reduce the non-specific cytotoxicity of neoplastic agents, targeted drug delivery systems may be used, in which the active compound is conjugated to a homing device. Homing may be mediated by proteins (e.g. antibodies) or peptides (e.g. hormone peptides) that recognize tumors with high specificity. The concept of selective drug targeting is based on the high expression of certain cell surface components on tumors or the tumor neovasculature [1]. One of the cancer specific receptors is aminopeptidase N (APN or CD13).
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