The conjugation of high-affinity cRGD-containing peptides is a promising approach in nanomedicine to efficiently reduce off-targeting effects and enhance the cellular uptake by integrin-overexpressing tumor cells. Herein we utilize atomistic molecular dynamics simulations to evaluate key structural–functional parameters of these targeting ligands for an effective binding activity towards αVβ3 integrins. An increasing number of cRGD ligands is conjugated to PEG chains grafted to highly curved TiO2 nanoparticles to unveil the impact of cRGD density on the ligand's presentation, stability, and conformation in an explicit aqueous environment. We find that a low density leads to an optimal spatial presentation of cRGD ligands out of the “stealth” PEGylated layer around the nanosystem, favoring a straight upward orientation and spaced distribution of the targeting ligands in the bulk-water phase. On the contrary, high densities favor over-clustering of cRGD ligands, driven by a concerted mechanism of enhanced ligand–ligand interactions and reduced water accessibility over the ligand's molecular surface. These findings strongly suggest that the ligand density modulation is a key factor in the design of cRGD-targeting nanodevices to maximize their binding efficiency into over-expressed αVβ3 integrin receptors.

Siani, P., Frigerio, G., Donadoni, E., Di Valentin, C. (2022). Molecular dynamics simulations of cRGD-conjugated PEGylated TiO$_{2}$ nanoparticles for targeted photodynamic therapy. JOURNAL OF COLLOID AND INTERFACE SCIENCE, 627(December 2022), 126-141 [10.1016/j.jcis.2022.07.045].

Molecular dynamics simulations of cRGD-conjugated PEGylated TiO$_{2}$ nanoparticles for targeted photodynamic therapy

Siani, Paulo;Frigerio, Giulia;Donadoni, Edoardo;Di Valentin, Cristiana
2022

Abstract

The conjugation of high-affinity cRGD-containing peptides is a promising approach in nanomedicine to efficiently reduce off-targeting effects and enhance the cellular uptake by integrin-overexpressing tumor cells. Herein we utilize atomistic molecular dynamics simulations to evaluate key structural–functional parameters of these targeting ligands for an effective binding activity towards αVβ3 integrins. An increasing number of cRGD ligands is conjugated to PEG chains grafted to highly curved TiO2 nanoparticles to unveil the impact of cRGD density on the ligand's presentation, stability, and conformation in an explicit aqueous environment. We find that a low density leads to an optimal spatial presentation of cRGD ligands out of the “stealth” PEGylated layer around the nanosystem, favoring a straight upward orientation and spaced distribution of the targeting ligands in the bulk-water phase. On the contrary, high densities favor over-clustering of cRGD ligands, driven by a concerted mechanism of enhanced ligand–ligand interactions and reduced water accessibility over the ligand's molecular surface. These findings strongly suggest that the ligand density modulation is a key factor in the design of cRGD-targeting nanodevices to maximize their binding efficiency into over-expressed αVβ3 integrin receptors.
Articolo in rivista - Articolo scientifico
Cyclic RGD; Integrin; Ligand conformation; Ligand density; Ligand presentation; Molecular dynamics; Nanomedicine; Nanoparticles; PEG; Targeting; Titanium dioxide;
English
126
141
16
Siani, P., Frigerio, G., Donadoni, E., Di Valentin, C. (2022). Molecular dynamics simulations of cRGD-conjugated PEGylated TiO$_{2}$ nanoparticles for targeted photodynamic therapy. JOURNAL OF COLLOID AND INTERFACE SCIENCE, 627(December 2022), 126-141 [10.1016/j.jcis.2022.07.045].
Siani, P; Frigerio, G; Donadoni, E; Di Valentin, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/391284
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