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

Autor: Beatrice Eymin, Titouan Montheil, Thibault Jacquet, Manon Maurel, Tao Jia, Jéremy Ciccione, Jean Martinez, Ahmad Mehdi, Gilles Subra, Jean-Luc Coll
Přispěvatelé: Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Eymin, Beatrice, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Nitric Oxide Synthase Type III
Angiogenesis
Cell Survival
Integrin
Pharmaceutical Science
02 engineering and technology
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
030226 pharmacology & pharmacy
Peptides
Cyclic
Receptor tyrosine kinase
Polyethylene Glycols
03 medical and health sciences
0302 clinical medicine
Neuropilin 1
Human Umbilical Vein Endothelial Cells
Humans
Protein kinase B
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Cells
Cultured
[CHIM.MATE] Chemical Sciences/Material chemistry
Glycogen Synthase Kinase 3 beta
biology
Chemistry
Receptor Protein-Tyrosine Kinases
[CHIM.MATE]Chemical Sciences/Material chemistry
021001 nanoscience & nanotechnology
Silicon Dioxide
Cell biology
Endothelial stem cell
MESH: AKT
Homomultimer and heteromultimer targeting
IGF-1R/IR
α(v)ß(3) integrin
biology.protein
PEGylation
Nanoparticles
Signal transduction
0210 nano-technology
Oligopeptides
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: International Journal of Pharmaceutics
International Journal of Pharmaceutics, Elsevier, 2019, 568, pp.118507. ⟨10.1016/j.ijpharm.2019.118507⟩
International Journal of Pharmaceutics, 2019, 568, pp.118507. ⟨10.1016/j.ijpharm.2019.118507⟩
ISSN: 0378-5173
Popis: International audience; 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.
Databáze: OpenAIRE
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