期刊
BIOMATERIALS
卷 155, 期 -, 页码 64-79出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.10.042
关键词
Angiogenesis; Silica nanoparticles; alpha(v)beta(3) integrin; VEGFR2 antagonist; AKT; IGF-1R/IR; Homomultimer and heteromultimer targeting
资金
- China Scholarship Council
- Institut National du Cancer [INCA-PLBio16-085]
- Fondation ARC pour la Recherche sur le Cancer [PGA1-20160203791]
- LabEx
- Institut Carnot Chimie Balard
- LabEx, ChemiSyst [ANR-10-LabX-05-01]
- ITMO cancer
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- National Research Agency (France Live Imaging program grant Infrastructure d'avenir en Biologie Sante) [ANR-11-INBS-0006]
Angiogenesis strongly depends on the activation of integrins, especially integrin alpha(v)beta(3), 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/GSK3 beta/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 heter-omultivalent NPs with alpha(v)beta(3)-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. (C) 2017 Elsevier Ltd. All rights reserved.
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