Heteromultivalent targeting of integrin α v β 3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors

Biomaterials. 2018 Feb;155:64-79. doi: 10.1016/j.biomaterials.2017.10.042. Epub 2017 Oct 29.

Abstract

Angiogenesis strongly depends on the activation of integrins, especially integrin αvβ3, and of neuropilin-1 (NRP-1), a co-receptor of VEGFR2. Dual-targeted molecules that simultaneously block both of them are expected have increased anti-angiogenic and antitumor activity. Toward this goal, we generated bifunctional 40 nm-sized silica nanoparticles (NPs) coated with controlled amounts of cRGD and ATWLPPR peptides and studied their affinity, selectivity and biological activity in HUVECs. Sub-nanomolar concentrations of NPs grafted either with ATWLPPR alone or in combination with cRGD exhibit potent and specific antagonist activity against VEGFR2/AKT signaling. However, a 1 nM concentration of the cRGD/ATWLPPR-heteromultivalent particles (RGD/ATW-NPs) also blocks the phosphorylation of VEGFR2 while co-inducing an unexpected long-lasting activation of AKT via IGF-1R/IR-AKT/GSK3β/eNOS signaling that stimulates cell survival and abrogates the intrinsic toxicity of silica-NPs to serum-starved HUVECs. We also showed that their repeated intravenous administration was associated with the proliferation of human U87MG tumor cells engrafted in nude mice and a dilatation of the tumor blood vessels. We present biochemical evidence for the complex cross-talk generated by the binding of the heteromultivalent NPs with αvβ3-integrin and with NRP1. In particular, we show for the first time that such heteromultivalent NPs can trans-activate IGF-1/insulin receptors and exert dose-dependent pro-survival activity. This study demonstrates the difficulties in designing targeted silica-based NPs for antiangiogenic therapies and the possible risks posed by undesirable side effects.

Keywords: AKT; Angiogenesis; Homomultimer and heteromultimer targeting; IGF-1R/IR; Silica nanoparticles; VEGFR2 antagonist; α(v)ß(3) integrin.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Integrin alphaVbeta3 / metabolism*
  • Mice
  • Mice, Nude
  • Nanoparticles / chemistry
  • Neuropilin-1 / metabolism*
  • Oligopeptides / pharmacology
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / metabolism
  • Signal Transduction / drug effects
  • Silicon Dioxide / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Ala-Thr-Trp-Leu-Pro-Pro-Arg
  • Integrin alphaVbeta3
  • Oligopeptides
  • Neuropilin-1
  • Insulin-Like Growth Factor I
  • Silicon Dioxide
  • arginyl-glycyl-aspartic acid
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Vascular Endothelial Growth Factor Receptor-2