NGR-peptide-drug conjugates with dual targeting properties

• Published in: PloS one 2017-06, Vol.12 (6), p.e0178632-e0178632
• Main Authors: Enyedi, Kata Nóra, Tóth, Szilárd, Szakács, Gergely, Mező, Gábor
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Alternating current; Aminopeptidase; Angiogenesis; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Antibody-drug conjugates; Anticancer properties; Antineoplastic drugs; Antitumor activity; Antitumor agents; Arginine; Asparagine; Attachment; Binding; Biology and Life Sciences; Biotechnology; C-Terminus; Cancer research; Cancer therapies; Cancer treatment; CD13 antigen; Cell growth; Cell Line, Tumor; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Colon; Conjugates; Cyclization; Cytotoxicity; Daunomycin; Daunorubicin - chemistry; Daunorubicin - pharmacology; Decomposition; Dendritic branching; Derivatives; Drug delivery; Drug delivery systems; Drugs; Fibrosarcoma; Glycine; Health aspects; Homing; Humans; In vitro methods and tests; Integrins; Isoforms; Ligands; Medical research; Metastases; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides; Protein binding; Radioisotopes; Research and Analysis Methods; Science; Spectrometry, Mass, Electrospray Ionization; Stability; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178632

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.