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

Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors.

Author information

1
INSERM-UGA U1209, CNRS UMR5309, Institute for Advanced Biosciences, La Tronche, France.
2
Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS, Université de Montpellier, ENSCM, Montpellier, France.
3
Institut Charles Gerhardt, UMR5253, CNRS, Université de Montpellier, ENSCM, Montpellier Cedex 05, France.
4
INSERM-UGA U1209, CNRS UMR5309, Institute for Advanced Biosciences, La Tronche, France. Electronic address: jean-luc.coll@univ-grenoble-alpes.fr.

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

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