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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.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2019 Sep 10; Vol. 568, pp. 118507. Date of Electronic Publication: 2019 Jul 09. - Publication Year :
- 2019
-
Abstract
- 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 α <subscript>v</subscript> ß <subscript>3</subscript> (cRGD) <subscript>,</subscript> 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.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Cell Survival drug effects
Cells, Cultured
Glycogen Synthase Kinase 3 beta metabolism
Human Umbilical Vein Endothelial Cells metabolism
Humans
Nanoparticles chemistry
Nitric Oxide Synthase Type III metabolism
Oligopeptides chemistry
Peptides, Cyclic chemistry
Polyethylene Glycols chemistry
Proto-Oncogene Proteins c-akt metabolism
Receptor Protein-Tyrosine Kinases metabolism
Signal Transduction drug effects
Silicon Dioxide chemistry
Human Umbilical Vein Endothelial Cells drug effects
Nanoparticles administration & dosage
Oligopeptides administration & dosage
Peptides, Cyclic administration & dosage
Polyethylene Glycols administration & dosage
Silicon Dioxide administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3476
- Volume :
- 568
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31299336
- Full Text :
- https://doi.org/10.1016/j.ijpharm.2019.118507