NGR-peptide-drug conjugates with dual targeting properties

PLoS One. 2017 Jun 2;12(6):e0178632. doi: 10.1371/journal.pone.0178632. eCollection 2017.

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.

MeSH terms

  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Chromatography, Reverse-Phase
  • Cyclization
  • Daunorubicin / chemistry*
  • Daunorubicin / pharmacology
  • Humans
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Antibiotics, Antineoplastic
  • NGR peptide
  • Oligopeptides
  • Daunorubicin

Grants and funding

This project has received funding from the Hungarian National Science Fund (OTKA K 119552 and K 119552). G.Sz. was supported by a Momentum grant of the Hungarian Academy of Sciences.