Site preference and local structural stability of Bi(III) substitution in hydroxyapatite using first-principles simulations.

Bismuth (Bi(III)) substitution in hydroxyapatite (HAp) lattice confers unique properties such as antibacterial, catalytic, radiosensitization, and conductive properties while preserving the innate bioactivity. Understanding the local structural changes upon Bi3+ substitution is essential for controlling the stability and optimizing the properties of HAp. Despite numerous experimental studies, the precise substitution behaviors, such as site preference and structural stability, remain incompletely understood. In this study, the substitution behavior of Bi(III) into the HAp lattice with formula of Ca9Bi(PO4)6(O)(OH) was investigated via first-principles simulation by implementing density functional theory. Energy calculations showed that Bi3+ preferentially occupies the Ca(2) site with an energy difference of ∼0.02 eV per atom. Local structure analysis revealed higher bond population values and an oxygen coordination shift from 7 to 6 for the Ca(2) site, attributed to the greater covalent interactions and its flexible environment accommodating the bulky Bi3+ ion and its stereochemically active lone pair. This work provides the first comprehensive investigation on Bi3+ ion substitution site preference in HAp using first-principles simulations.

Folic acid-mediated enhancement of the diagnostic potential of luminescent europium-doped hydroxyapatite nanocrystals for cancer biomaging.

Early and accurate cancer diagnosis is crucial for improving patient survival rates. Luminescent nanoparticles have emerged as a promising tool in fluorescence bioimaging for cancer diagnosis. To enhance diagnostic accuracy, ligands promoting endocytosis into cancer cells are commonly incorporated onto nanoparticle surfaces. Folic acid (FA) is one such ligand, known to specifically bind to folate receptors (FR) overexpressed in various cancer cells such as cervical and ovarian carcinoma. Therefore, surface modification of luminescent nanoparticles with FA can enhance both luminescence efficiency and diagnostic accuracy. In this study, luminescent europium-doped hydroxyapatite (EuHAp) nanocrystals were prepared via hydrothermal method and subsequently modified with (3-Aminopropyl)triethoxysilane (APTES) followed by FA to target FR-positive human cervical adenocarcinoma cell line (HeLa) cells. The sequential grafting of APTES and then FA formed a robust covalent linkage between the nanocrystals and FA. Rod-shaped FA-modified EuHAp nanocrystals, approximately 100 nm in size, exhibited emission peaks at 589, 615, and 650 nm upon excitation at 397 nm. Despite a reduction in photoluminescence intensity following FA modification, fluorescence microscopy revealed a remarkable 120-fold increase in intensity compared to unmodified EuHAp, attributed to the enhanced uptake of FA-modified EuHAp. Additionally, confocal microscope observations confirmed the specificity and the internalization of FA-modified EuHAp nanocrystals in HeLa cells. In conclusion, the modification of EuHAp nanocrystals with FA presents a promising strategy to enhance the diagnostic potential of cancer bioimaging probes.

Adsorption of l-buthionine sulfoximine on Bi(III) and Eu(III) co-substituted hydroxyapatite nanocrystals for enhancing radiosensitization effects.

Cancer theranostics combines therapeutic and diagnostic capabilities into a single system to treat cancer efficiently. Biocompatible nanomaterials can be engineered to exhibit cancer theranostic functions, for instance radiosensitization and photoluminescence. In this study, trivalent Bi and Eu ions were co-substituted into the lattice of hydroxyapatite (Bi(III):Eu(III) HAp) to develop a cancer theranostic nanocrystal. Bi provides radiosensitization capabilities while Eu imparts photoluminescence properties. To complement the radiotherapeutic function, l-buthionine sulfoximine (l-BSO) was adsorbed onto the nanocrystal surface. l-BSO inhibits the biosynthesis of cellular antioxidants, which can enhance radiosensitization effects. The Bi(III):Eu(III) HAp nanocrystals were prepared via a hydrothermal method. Structural and compositional analyses showed that both Bi and Eu ions were substituted into the HAp lattice. l-BSO was adsorbed onto the surface via electrostatic interactions between the charged carboxyl and amino groups of l-BSO and the surface ions of the nanocrystals. The adsorption followed the Langmuir isotherm model, implying a homogeneous monolayer adsorption. The l-BSO adsorbed Bi(III):Eu(III) HAp nanocrystals were found to have negligible cytotoxicity except the setting with l-BSO adsorbed amounts of 0.44 µmol/m2. This l-BSO amount was found to be high enough to elicit cytotoxicity due to l-BSO being released and causing excessive antioxidant depletion. Gamma ray irradiation clearly activated the cytotoxicity of the samples and increased the cell death rate, confirming radiosensitization abilities. At a constant amount of nanocrystals, the cell death rate increases with l-BSO concentration. This indicates that l-BSO can enhance the radiosensitization effect of the Bi(III):Eu(III) HAp nanocrystals.