Monodisperse Core-Shell NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-GGGRGDSGGGY-NH2 Nanoparticles Excitable at 808 and 980 nm: Design, Surface Engineering, and Application in Life Sciences.

Uliana Kostiv,Miroslav Šlouf,Vladimír Proks,Daniel Horák,Hana Engstová,Artur Podhorodecki,Petr Ježek,Bartosz Krajnik

doi:10.3389/fchem.2020.00497

Abstract

Lanthanide-doped upconversion nanoparticles (UCNPs) have a unique capability of upconverting near-infrared (NIR) excitation into ultraviolet, visible, and NIR emission. Conventional UCNPs composed of NaYF4:Yb3+/Er3+(Tm3+) are excited by NIR light at 980 nm, where undesirable absorption by water can cause overheating or damage of living tissues and reduce nanoparticle luminescence. Incorporation of Nd3+ ions into the UCNP lattice shifts the excitation wavelength to 808 nm, where absorption of water is minimal. Herein, core-shell NaYF4:Yb3+/Er3+@NaYF4:Nd3+ nanoparticles, which are doubly doped by sensitizers (Yb3+ and Nd3+) and an activator (Er3+) in the host NaYF4 matrix, were synthesized by high-temperature coprecipitation of lanthanide chlorides in the presence of oleic acid as a stabilizer. Uniform core (24 nm) and core-shell particles with tunable shell thickness (~0.5–4 nm) were thoroughly characterized by transmission electron microscopy (TEM), energy-dispersive analysis, selected area electron diffraction, and photoluminescence emission spectra at 808 and 980 nm excitation. To ensure dispersibility of the particles in biologically relevant media, they were coated by in-house synthesized poly(ethylene glycol) (PEG)-neridronate terminated with an alkyne (Alk). The stability of the NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-Alk nanoparticles in water or 0.01 M PBS and the presence of PEG on the surface were determined by dynamic light scattering, ζ-potential measurements, thermogravimetric analysis, and FTIR spectroscopy. Finally, the adhesive azidopentanoyl-modified GGGRGDSGGGY-NH2 (RGDS) peptide was immobilized on the NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-Alk particles via Cu(I)-catalyzed azide-alkyne cycloaddition. The toxicity of the unmodified core-shell NaYF4:Yb3+/Er3+@NaYF4:Nd3+, NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-Alk, and NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-RGDS nanoparticles on both Hep-G2 and HeLa cells was determined, confirming no adverse effect on their survival and proliferation. The interaction of the nanoparticles with Hep-G2 cells was monitored by confocal microscopy at both 808 and 980 nm excitation. The NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-RGDS nanoparticles were localized on the cell membranes due to specific binding of the RGDS peptide to integrins, in contrast to the NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-Alk particles, which were not engulfed by the cells. The NaYF4:Yb3+/Er3+@NaYF4:Nd3+-PEG-RGDS nanoparticles thus appear to be promising as a new non-invasive probe for specific bioimaging of cells and tissues. This development makes the nanoparticles useful for diagnostic and/or, after immobilization of a bioactive compound, even theranostic applications in the treatment of various fatal diseases.

Highlights

Lanthanide-doped upconversion nanoparticles (UCNPs) have recently attracted a great deal of attention as promising materials for various biomedical applications including medical diagnostics, mainly for in vitro and in vivo imaging, and in longer perspective for drug and gene delivery, and photothermal and photodynamic therapy of malignancies (Duan et al, 2018; Qin et al, 2019)
Synthesis and Structure of NaYF4:Yb3+/Er3+ Core and NaYF4:Yb3+/Er3+@NaYF4:Nd3+ Core-Shell Nanoparticles. Both the starting NaYF4:Yb3+/Er3+ core and NaYF4:Yb3+/Er3+@NaYF4:Nd3+ core-shell nanoparticles were synthesized in a high-boiling organic solvent in the presence of oleic acid (OA) as a stabilizer by high-temperature coprecipitation of lanthanide chlorides with different amounts of shell precursors
The hexagonal β-NaYF4 phase of NaYF4:Yb3+/Er3+@NaYF4:Nd3+ core-shell nanoparticles was successfully synthesized by thermal coprecipitation of lanthanide precursors

Summary

Introduction

Lanthanide-doped upconversion nanoparticles (UCNPs) have recently attracted a great deal of attention as promising materials for various biomedical applications including medical diagnostics, mainly for in vitro and in vivo imaging, and in longer perspective for drug and gene delivery, and photothermal and photodynamic therapy of malignancies (Duan et al, 2018; Qin et al, 2019). Interest in the UCNPs comes from their superior optical properties, such as a narrow line emission, long luminescence lifetime, high photostability, and absence of background fluorescence interference (Wolfbeis, 2015). The main advantage of UCNPs is in their ability to convert low energy excitation photons (i.e., from NIR spectral range), which can penetrate deeper into biological tissues (up to 5 cm) (Li et al, 2017) than visible light, to high-energy photons, e.g., ultraviolet or visible, via anti-Stokes emission (Zhu et al, 2017). UCNPs are characterized with low absorption and scattering rate. In contrast to the high energetic photons, NIR light is not harmful for the tissue and do not induce autofluoroscence, which provides significant contrast improvement

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