Heteromultivalent整合素α靶向的<sub>v</sub> β <sub>3</sub>和神经毡蛋白1经由IGF1 /胰岛素受体的激活促进细胞存活,Biomaterials

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Heteromultivalent整合素α靶向的_v β ₃和神经毡蛋白1经由IGF1 /胰岛素受体的激活促进细胞存活
Biomaterials ( IF 12.8 ) Pub Date : 2017-10-29 , DOI: 10.1016/j.biomaterials.2017.10.042
Tao Jia , Jungyoon Choi , Jéremy Ciccione , Maxime Henry , Ahmad Mehdi , Jean Martinez , Béatrice Eymin , Gilles Subra , Jean-Luc Coll

血管发生强烈地依赖于整联的激活，特别是整合素α _v β ₃，以及VEGFR2的共同受体Neuropilin-1（NRP-1）。预期同时阻断它们的双靶分子具有增加的抗血管生成和抗肿瘤活性。为了实现这一目标，我们生成了包覆有受控量的cRGD和ATWLPPR肽的双功能40 nm大小的二氧化硅纳米颗粒（NP），并研究了它们在HUVEC中的亲和力，选择性和生物活性。单独与ATWLPPR或与cRGD结合移植的亚纳摩尔浓度的NPs对VEGFR2 / AKT信号传导均表现出有效的特异性拮抗活性。然而，1 nM浓度的cRGD / ATWLPPR异多价颗粒（RGD / ATW-NPs）也会阻断VEGFR2的磷酸化，同时通过IGF-1R / IR-AKT /GSK3β/ eNOS信号共同诱导AKT出乎意料的持久活化可以刺激细胞存活并消除二氧化硅纳米颗粒对缺乏血清的HUVEC的内在毒性。我们还表明，它们的重复静脉内给药与裸鼠中移植的人U87MG肿瘤细胞的增殖和肿瘤血管的扩张有关。 α_v β ₃整合素，并用NRP1。特别是，我们首次证明了这种异多价NP可以反式激活IGF1R并发挥剂量依赖性的生存前活性。这项研究表明，在设计针对抗血管生成疗法的靶向二氧化硅基NP方面存在困难，而且不良副作用可能带来风险。

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Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF1/insulin receptors

Angiogenesis strongly depends on the activation of integrins, especially integrin α_vβ₃, 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 α_vβ₃-integrin and with NRP1. In particular, we show for the first time that such heteromultivalent NPs can trans-activate IGF1R 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.

更新日期：2017-10-30

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