Molecular dynamics simulations of cRGD-conjugated PEGylated TiO$_2$ nanoparticles for targeted photodynamic therapy

TL;DR

This study uses molecular dynamics simulations to analyze how cRGD ligand density on PEGylated TiO2 nanoparticles affects their structural presentation and potential targeting efficiency for tumor cells overexpressing $ ext{α}_Veta_3$ integrins.

Contribution

It provides detailed insights into how ligand density influences ligand orientation, clustering, and stability, guiding the design of more effective targeted nanomedicines.

Findings

Low ligand density promotes optimal ligand presentation and orientation.

High ligand density causes clustering and internalization of ligands.

Ligand density modulation is crucial for maximizing targeting efficiency.

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 $\alpha_V\beta_3$ integrins. An increasing number of cRGD ligands is conjugated to PEG chains grafted to highly curved TiO$_2$ 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 clustering and internalization of cRGD ligands in the inner region of the PEGylated layer, 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 $\alpha_V\beta_3$ integrin receptors.