Multi-scale modeling of folic acid-functionalized TiO$_{2}$ nanoparticles for active targeting of tumor cells

TL;DR

This study uses computational modeling to compare direct and PEG-spaced folic acid attachment on TiO2 nanoparticles, revealing how these configurations affect stability and targeting ligand exposure for tumor cell targeting.

Contribution

It combines quantum mechanics and molecular dynamics to optimize and analyze folic acid functionalization on TiO2 nanoparticles, providing insights into the effects of PEG spacers on targeting efficiency.

Findings

FA-functionalized TiO2 NPs are chemically stable up to 500 K

PEG spacers influence FA exposure and intermolecular interactions

Optimal FA density depends on anchoring mode and spacer presence

Abstract

Strategies based on the active targeting of tumor cells are emerging as smart and efficient nanomedical procedures. Folic acid (FA) is a vitamin and a well-established tumor targeting agent because of its strong affinity for the folate receptor (FR), which is an overexpressed protein on the cell membranes of the tumor cells. FA can be successfully anchored to several nanocarriers, including inorganic nanoparticles (NPs) based on transition metal oxides. Among them, TiO$_{2}$ is extremely interesting because of its excellent photoabsorption and photocatalytic properties, which can be exploited in photodynamic therapy. However, it is not yet clear in which respects direct anchoring of FA to the NP or the use of spacers, based on polyethylene glycol (PEG) chains, are different and whether one approach is better than the other. In this work, we combine Quantum Mechanics (QM) and Classical Molecular Dynamics (MD) to design and optimize the FA functionalization on bare and PEGylated TiO$_{2}$ models and to study the dynamical behavior of the resulting nanoconjugates in pure water environment and in physiological conditions. We observe that they are chemically stable, even under the effect of increasing temperature (up to 500 K). Using the results from long MD simulations (100 ns) and from free energy calculations, we determine how the density of FA molecules on the TiO$_{2}$ NP and the presence of PEG spacers impact on the actual exposure of the ligands, especially by affecting the extent of FA-FA intermolecular interactions, which are detrimental for the targeting ability of FA towards the folate receptor. This analysis provides a solid and rational basis for experimentalists to define the optimal FA density and the more appropriate mode of anchoring to the carrier, according to the final purpose of the nanoconjugate.