The presence of PEG on nanoparticles presenting the c[RGDfK]- and/or ATWLPPR peptides deeply affects the RTKs-AKT-GSK3β-eNOS signaling pathway and endothelial cells survival - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue International Journal of Pharmaceutics Année : 2019

The presence of PEG on nanoparticles presenting the c[RGDfK]- and/or ATWLPPR peptides deeply affects the RTKs-AKT-GSK3β-eNOS signaling pathway and endothelial cells survival

Résumé

Covering the surface of a nanoparticle with polyethylene glycol (PEG) is a common way to prevent non-specific interactions but how its presence impacts on the activity of targeting ligands is still poorly documented. We synthesized a set of 9 silica nanoparticles grafted with c[RGDfK]-, a peptide targeting integrin αvß3 (cRGD), and/or with ATWLPPR, an anti-neuropilin 1 peptide (ATW). We then added various PEGs, and studied NPs binding on primary endothelial cells, the downstream activated signaling pathways and the impact on apoptosis. Our results show that the presence of PEG2000 on cRGD/ATW nanoparticles moderately improves cell binding but induces a 6000 times augmentation of AKT-dependent cell response due to the recruitment of other Receptor Tyrosine Kinases. Augmenting the length of the spacer that separates the peptides from the silica (using PEG3000) mainly resulted in a loss of specificity. Finally, the PEG-mediated hyperactivation of AKT did not protect endothelial cell from dying in the absence of serum, while its moderate activation obtained without PEG did. Finally, PEGylation of cRGD/ATW-NPs can generate nanoparticles with potent capacities to activate the AKT-GSK3β-eNOS cascade and to affect the resistance of endothelial cells to apoptosis. Thus, the impact of PEGylation should be precisely considered in order to avoid the apparition of counter-productive biological responses.
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Dates et versions

inserm-02337436 , version 1 (29-10-2019)

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Tao Jia, Jéremy Ciccione, Thibault Jacquet, Manon Maurel, Titouan Montheil, et al.. The presence of PEG on nanoparticles presenting the c[RGDfK]- and/or ATWLPPR peptides deeply affects the RTKs-AKT-GSK3β-eNOS signaling pathway and endothelial cells survival. International Journal of Pharmaceutics, 2019, 568, pp.118507. ⟨10.1016/j.ijpharm.2019.118507⟩. ⟨inserm-02337436⟩
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