Molecular dynamics simulations of cRGD-conjugated PEGylated TiO2 nanoparticles for targeted photodynamic therapy

Active targeting strategies, exploiting the biological interaction between ligands on the surface of nanoparticles and the cell targets, are known to increase the therapeutic efficacy of cancer treatments with respect to passive targeting strategies that are mainly based on the enhanced permeability and retention effect of tumor cells [1]. Thus, the conjugation of nanoparticles with cyclic RGD (cRGD) peptides affine to αVβ3 integrins is a promising approach in nanomedicine to efficiently reduce off-targeting effects and enhance the cellular uptake by integrin-overexpressing tumour cells [2]. We used atomistic molecular dynamics simulations to evaluate key structural-functional parameters of cRGD-conjugated TiO2 nanoparticles [3] for an effective binding activity towards αVβ3 integrins. An increasing number of cRGD ligands has been conjugated to PEG chains, grafted to highly curved TiO2 nanoparticles, to unveil the impact of cRGD density on its presentation, diffusion, and conformation in an explicit aqueous environment. Our findings strongly suggest that the ligand density modulation is a key factor in the design of cRGD-targeting nanodevices to maximize their binding efficiency to over-expressed αVβ3 integrins [4]. [1] S. Wilhelm, A.J. Tavares, Q. Dai, S. Ohta, J. Audet, H.F. Dvorak and W.C.W. Chan, Nat. Rev. Mater., 2016, 1, 16014. [2] F. Danhier, A. le Breton and V. Préat., Mol. Pharm., 2012, 9, 2961. [3] T. Rajh, N.M. Dimitrijevic, M. Bissonnette, T. Koritarov and V. Konda, Chem. Rev., 2014, 114, 10177. [4] P. Siani, G. Frigerio, E. Donadoni, C. Di Valentin, J. Colloid Interface Sci., 2022, 627, 126.