Doped Zinc Oxide Nanoparticles: Synthesis, Characterization and Potential Use in Nanomedicine

Abstract

Smart nanoparticles for medical applications have gathered considerable attention due to an improved biocompatibility and multifunctional properties useful in several applications, including advanced drug delivery systems, nanotheranostics and in vivo imaging. Among nanomaterials, zinc oxide nanoparticles (ZnO NPs) were deeply investigated due to their peculiar physical and chemical properties. The large surface to volume ratio, coupled with a reduced size, antimicrobial activity, photocatalytic and semiconducting properties, allowed the use of ZnO NPs as anticancer drugs in new generation physical therapies, nanoantibiotics and osteoinductive agents for bone tissue regeneration. However, ZnO NPs also show a limited stability in biological environments and unpredictable cytotoxic effects thereof. To overcome the abovementioned limitations and further extend the use of ZnO NPs in nanomedicine, doping seems to represent a promising solution. This review covers the main achievements in the use of doped ZnO NPs for nanomedicine applications. Sol-gel, as well as hydrothermal and combustion methods are largely employed to prepare ZnO NPs doped with rare earth and transition metal elements. For both dopant typologies, biomedical applications were demonstrated, such as enhanced antimicrobial activities and contrast imaging properties, along with an improved biocompatibility and stability of the colloidal ZnO NPs in biological media. The obtained results confirm that the doping of ZnO NPs represents a valuable tool to improve the corresponding biomedical properties with respect to the undoped counterpart, and also suggest that a new application of ZnO NPs in nanomedicine can be envisioned.

Keywords: antibacterial properties; bioimaging; doped ZnO; drug delivery; rare earth; theranostics; transition metals; zinc oxide nanoparticles.

Figure 1. Main applications of doped ZnO nanoparticles in nanomedicine.

Figure 2. Photoluminescence properties of Tb-doped ZnO nanotubes.

(a) Emission spectra of ZnO with different dopa nt levels excited by 235 nm radiation; (b) energy-levels schematic with the electron transition processes in Tb-doped ZnO nanotubes grown onto alumina. Adapted from [114].

Figure 3

Possible morphologies of ZnO nanostructured systems. From left to right and from top to bottom: nanoflowers (adapted from ref. [149]), nanopods (adapted from ref. [147]), nanorods (adapted from ref. [148]), mesoporous films, spherical nanoparticles, nanoneedles (adapted from ref. [150]), hollow microcolumns (adapted from ref. [151]), and micropods (adapted from ref. [152]).

Figure 4

Characterization of gadolinium-doped ZnO nanoparticles. From left to right and top to bottom: XRD patterns and Fourier transform infrared spectroscopy (I^rTIR) spectra of the nanostructures at different doping levels, scanning electron microscope and transmission electron microscope images of 3% Gd-doped ZnO nanoparticles. Adapted from ref. [177].

Figure 5. SEM images and antimicrobial performances of Cu- and Ag-doped nanoplates Adapted from ref. [152].

Figure 6

Au- and Ag-doped nanoparticles synthesized through a combustion method. On the left is the XRD patterns of the resulting particles, highlighting the presence of further peaks related to the secondary phases. On the right, the corresponding scanning electron microscope images of Ag-doped (a) and Au-doped (b) nanoparticles. Adapted from ref. [134].

Figure 7. Zinc release in an aqueous solution at pH 7 by the dissolution of Fe-doped ZnO nanoparticles at different doping levels Adaeted from ref. [128].

Figure 8

Fluorescence microscopy images of different cell lines exposed to differently Fe-doped ZnO nanoparticles (no nanoparticles (NPs) are present in the control samples). The green signal is related to Zn²⁺ free ions (FluoZin3-AM binds to ions and have a green fluorescent emission), the blue signal is related to the presence of cell nuclei. Less doped ZnO nanoparticles lead to a higher concentration of free zinc ions. Adapted from ref. [204].

Figure 9. Schematic reporting the main ZnO toxicity mechanisms that make this material an effective antimicrobial agent Adapted from ref. [232].

Figure 10. Tumor growth trend in mice at different times and differently doped ZnO nanoparticles.Tumor growth is reduced with 2% Fe-doped ZnO nanoparticfes. Adapted from ref. [204].

Figure 11

Photodynamic therapy mechanism. The photosensitizer (PS) is excited by external radiation, the excited electron may decay through different phenomena which may end in the generation of cytotoxic species, like ROS. Adapted from ref. [284].

Figure 12

Cell viability of different cell lines exposed to different illumination sources and different concentrations, incubated with pure, Gd-doped and Eu-doped ZnO nanoparticles. Adapted from ref. [164].

Figure 13

TEM images showing the internalization of pure (a) and Gd-doped (b) ZnO nanoparticles in lung carcinoma (SKLC-6) cells. Adaptedfrom ref. [286].