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.

Department of Experimental Physics Wroclaw University of Science and Technology Wroclaw Poland

Institute of Macromolecular Chemistry of the Czech Academy of Sciences Prague Czechia

Institute of Physiology of the Czech Academy of Sciences Prague Czechia

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Andrews K. W., Dyson D. J., Keown S. R. (1967). Interpretation of Electron Diffraction Patterns. New York, NY: Plenum Press.

Arppe R., Hyppänen I., Perälä N., Peltomaa R., Kaiser M., Würth C., et al. . (2015). Quenching of the upconversion luminescence of NaYF4:Yb3+,Er3+ and NaYF4:Yb3+,Tm3+ nanophosphors by water: the role of the sensitizer Yb3+ in non-radiative relaxation. Nanoscale 7, 11746–11757. 10.1039/C5NR02100F PubMed DOI

Auzel F. (2004). Upconversion and anti-stokes processes with f and d ions in solids. Chem. Rev. 104, 139–173. 10.1021/cr020357g PubMed DOI

Bagheri N., Liu Q., Bergstrand J., Pu R., Zhan Q., Ara M. H. M., et al. (2019). Change in the emission saturation and kinetics of upconversion nanoparticles under different light irradiations. Opt. Mater. 97:109389 10.1016/j.optmat.2019.109389 DOI

Beeston B. E. P., Horne R., Markham R. (1972). Electron Diffraction and Optical Diffraction Techniques. Amsterdam: North-Holland Publishing Company.

Chen G., Damasco J., Qiu H., Shao W., Ohulchanskyy T. Y., Valiev R. R., et al. . (2015). Energy-cascaded upconversion in an organic dye-sensitized core/shell fluoride nanocrystal. Nano Lett. 15, 7400–7407. 10.1021/acs.nanolett.5b02830 PubMed DOI PMC

Chen G., Qiu H., Prasad P. N., Chen X. (2014). Upconversion nanoparticles: design, nanochemistry, and applications in theranostics. Chem. Rev. 114, 5161–5214. 10.1021/cr400425h PubMed DOI PMC

Duan C., Liang L., Li L., Zhang R., Xu Z. P. (2018). Recent progress in upconversion luminescence nanomaterials for biomedical applications. J. Mater. Chem. B 6, 192–209. 10.1039/C7TB02527K PubMed DOI

Gee A., Xu X. (2018). Surface functionalisation of upconversion nanoparticles with different moieties for biomedical applications. Surfaces 1, 96–121. 10.3390/surfaces1010009 DOI

Glasser L. (2016). Crystallographic information resources. J. Chem. Educ. 93, 542–549. 10.1021/acs.jchemed.5b00253 DOI

Guerrero-Martinez A., Perez-Juste J., Liz-Marzan L. M. (2010). Recent progress on silica coating of nanoparticles and related nanomaterials. Adv. Mater. 22, 1182–1195. 10.1002/adma.200901263 PubMed DOI

Kostiv U., Janoušková O., Šlouf M., Kotov N., Engstová H., Smolková K., et al. . (2015). Silica-modified monodisperse hexagonal lanthanide nanocrystals: Synthesis and biological properties. Nanoscale 7, 18096–18104. 10.1039/C5NR05572E PubMed DOI

Kostiv U., Kotelnikov I., Proks V., Šlouf M., Kučka J., Engstová H., et al. . (2016). RGDS- and TAT-conjugated upconversion NaYF4:Yb3+/Er3+@SiO2 nanoparticles: In vitro human epithelioid cervix carcinoma cellular uptake, imaging and targeting. ACS Appl. Mater. Interfaces 8, 20422–20431. 10.1021/acsami.6b07291 PubMed DOI

Kostiv U., Lobaz V., Kučka J., Švec P., Sedláček O., Hrubý M., et al. . (2017c). A simple neridronate-based surface coating strategy for upconversion nanoparticles: Highly colloidally stable 125I-radiolabeled NaYF4:Yb3+/Er3+@PEG nanoparticles for multimodal in vivo tissue imaging. Nanoscale 9, 16680–16688. 10.1039/C7NR05456D PubMed DOI

Kostiv U., Patsula V., Noculak A., Podhorodecki A., Větvička D., Poučková P., et al. . (2017a). Phthalocyanine-conjugated upconversion NaYF4:Yb3+/Er3+@SiO2 nanospheres for NIR-triggered photodynamic therapy in a tumor mouse model. ChemMedChem 12, 2066–2073. 10.1002/cmdc.201700508 PubMed DOI

Kostiv U., Rajsiglová L., Luptáková D., Pluháček T., Vannucci L., Havlíček V., et al. (2017b). Biodistribution of upconversion/magnetic silica-coated NaGdF4:Yb3+/Er3+ nanoparticles in mouse models. RSC Adv. 7, 45997–46006. 10.1039/C7RA08712H DOI

Kraus W., Nolze G. (1996). POWDER CELL - a program for the representation and manipulation of crystal structures and calculation of the resulting X-ray powder patterns. J. Appl. Cryst. 29, 301–303. 10.1107/S0021889895014920 DOI

Lábár J. L. (2005). Consistent indexing of a (set of) SAED pattern(s) with the ProcessDiffraction program. Ultramicroscopy 103, 237–249. 10.1016/j.ultramic.2004.12.004 PubMed DOI

Lahtinen S., Lyytikäinen A., Päkkilä H., Hömppi E., Perälä N., Lastusaari M., et al. (2017). Disintegration of hexagonal NaYF4:Yb3+,Er3+ upconverting nanoparticles in aqueous media: the role of fluoride in solubility equilibrium. J. Phys. Chem. C 121, 656–665. 10.1021/acs.jpcc.6b09301 DOI

Lai J., Zhang Y., Pasquale N., Lee K. B. (2014). An upconversion nanoparticle with orthogonal emissions using dual NIR excitations for controlled two-way photoswitching. Angew. Chem. 126, 14647–14651. 10.1002/ange.201408219 PubMed DOI PMC

Li T., Xue C., Wang P., Li Y., Wu L. (2017). Photon penetration depth in human brain for light stimulation and treatment: a realistic Monte Carlo simulation study. J. Innov. Opt. Health Sci. 10:17430027 10.1142/S1793545817430027 DOI

Liu X., Zhao J., Sun Y., Song K., Yu Y., Du C., et al. . (2009). Ionothermal synthesis of hexagonal-phase NaYF4:Yb3+,Er3+/Tm3+ upconversion nanophosphors. Chem. Commun. 43, 6628–6630. 10.1039/b915517a PubMed DOI

Lowry G. V., Hill R. J., Harper S., Rawle A. F., Hendren C. O., Klaessig F., et al. (2016). Guidance to improve the scientific value of zeta-potential measurements in nanoEHS. Environ. Sci. Nano 3, 953–965. 10.1039/C6EN00136J DOI

Luwang M. N., Ningthoujam R. S., Jagannath Srivastava S. K., Vatsa R. K. (2010). Effects of Ce3+ codoping and annealing on phase transformation and luminescence of Eu3+-doped YPO4 nanorods: D2O solvent effect. J. Am. Chem. Soc. 132, 2759–2768. 10.1021/ja909578s PubMed DOI

Mandl G. A., Cooper D. R., Hirsch T., Seuntjens J., Capobianco J. A. (2019). Perspective: lanthanide-doped upconverting nanoparticles. Methods Appl. Fluoresc. 7:012004. 10.1088/2050-6120/aafa3d PubMed DOI

Mickert M. J., Farka Z., Kostiv U., Hlaváček A., Horák D., Skládal P., et al. . (2019). Measurement of sub-femtomolar concentrations of prostate-specific antigen through single-molecule counting with an upconversion-linked immunosorbent assay. Anal. Chem. 91, 9435–9441. 10.1021/acs.analchem.9b02872 PubMed DOI

Muhr V., Wilhelm S., Hirsch T., Wolfbeis O. S. (2014). Upconversion nanoparticles: from hydrophobic to hydrophilic surfaces. Acc. Chem. Res. 47, 3481–3493. 10.1021/ar500253g PubMed DOI

Naccache R., Yu Q., Capobianco J. A. (2015). The fluoride host: Nucleation, growth, and upconversion of lanthanide-doped nanoparticles. Adv. Optical. Mater. 3, 482–509. 10.1002/adom.201400628 DOI

Patsula V., Horák D., Kučka J., Macková H., Lobaz V., Francová P., et al. (2019). Synthesis and modification of uniform PEG-neridronate-modified magnetic nanoparticles determines prolonged blood circulation and biodistribution in a mouse preclinical model. Sci. Rep. 9:10765 10.1038/s41598-019-47262-w PubMed DOI PMC

Plohl O., Kralj S., Majaron B., Fröhlich E., Ponikvar-Svet M., Makovec D., et al. . (2017). Amphiphilic coatings for the protection of upconverting nanoparticles against dissolution in aqueous media. Dalton Trans. 46, 6975–6984. 10.1039/C7DT00529F PubMed DOI

Podhorodecki A., Krajnik B., Golacki L. W., Kostiv U., Pawlik G., Kaczmarek M., et al. . (2018). Percolation limited emission intensity from upconverting NaYF4:Yb3+,Er3+ nanocrystals – a single nanocrystal optical study. Nanoscale 10, 21186–21196. 10.1039/C8NR05961F PubMed DOI

Poláchová V., Pastucha M., Mikušová Z., Mickert M. J., Hlaváček A., Gorris H. H., et al. . (2019). Click-conjugated photon-upconversion nanoparticles in an immunoassay for honeybee pathogen Melissococcus plutonius. Nanoscale 11, 8343–8351. 10.1039/C9NR01246J PubMed DOI

Proks V., Jaros J., Pop-Georgievski O., Kucka J., Popelka S., Dvorak P., et al. . (2012). “Click & seed” approach to the biomimetic modification of material surfaces. Macromol. Biosci. 12, 1232–1242. 10.1002/mabi.201200095 PubMed DOI

Qin X., Xu J., Wu Y., Liu X. (2019). Energy-transfer editing in lanthanide-activated upconversion nanocrystals: a toolbox for emerging applications. ACS Cent. Sci. 5, 29–42. 10.1021/acscentsci.8b00827 PubMed DOI PMC

Sedlmeier A., Gorris H. H. (2015). Surface modification and characterization of photon-upconverting nanoparticles for bioanalytical applications. Chem. Soc. Rev. 44, 1526–1560. 10.1039/C4CS00186A PubMed DOI

Shameli K., Ahmad M. B., Jazayeri S. D., Sedaghat S., Shabanzadeh P., Jahangirian H., et al. . (2012). Synthesis and characterization of polyethylene glycol mediated silver nanoparticles by the green method. Int. J. Mol. Sci. 13, 6639–6650. 10.3390/ijms13066639 PubMed DOI PMC

Shukla N., Liu C., Jones P. M., Weller D. (2003). FTIR study of surfactant bonding to FePt nanoparticles. J. Magn. Magn. Mater. 266, 178–184. 10.1016/S0304-88530300469-4 DOI

Stöber W., Fink A. (1968). Controlled growth of monodisperse silica spheres in the micron size range. J. Colloid Interface Sci. 26, 62–69. 10.1016/0021-97976890272-5 DOI

Wang M., Abbineni G., Clevenger A., Mao C., Xu S. (2011). Upconversion nanoparticles: synthesis, surface modification and biological applications. Nanomedicine 7, 710–729. 10.1016/j.nano.2011.02.013 PubMed DOI PMC

Wang R., Li X., Zhou L., Zhang F. (2014). Epitaxial seeded growth of rare-earth nanocrystals with efficient 800 nm near-infrared to 1525 nm short-wavelength infrared downconversion photoluminescence for in vivo bioimaging. Angew. Chem. 126, 12282–12286. 10.1002/ange.201407420 PubMed DOI

Wiesholler L. M., Frenzel F., Grauel B., Würth C., Resch-Genger U., Hirsch T. (2019). Yb,Nd,Er-doped upconversion nanoparticles: 980 nm versus 808 nm excitation. Nanoscale 11, 13440–13449. 10.1039/C9NR03127H PubMed DOI

Wilhelm S. (2017). Perspectives for upconverting nanoparticles. ACS Nano 11, 10644–10653. 10.1021/acsnano.7b07120 PubMed DOI

Wilhelm S., Kaiser M., Würth C., Heiland J., Carrillo-Carrion C., Muhr V., et al. . (2015). Water dispersible upconverting nanoparticles: effects of surface modification on their luminescence and colloidal stability. Nanoscale 7, 1403–1410. 10.1039/C4NR05954A PubMed DOI

Wolfbeis O. S. (2015). An overview of nanoparticles commonly used in fluorescent bioimaging. Chem. Soc. Rev. 44, 4743–4768. 10.1039/C4CS00392F PubMed DOI

Zhan Q., Qian J., Liang H., Somesfalean G., Wang D., He S., et al. . (2011). Using 915 nm laser excited Tm3+/Er3+/Ho3+-doped NaYbF4 upconversion nanoparticles for in vitro and deeper in vivo bioimaging without overheating irradiation. ACS Nano 5, 3744–3757. 10.1021/nn200110j PubMed DOI

Zhang Z., Shikha S., Liu J., Zhang J., Mei Q., Zhang Y. (2019). Upconversion nanoprobes: recent advances in sensing applications. Anal. Chem. 91, 548–568. 10.1021/acs.analchem.8b04049 PubMed DOI

Zhou B., Shi B., Jin D., Liu X. (2015). Controlling upconversion nanocrystals for emerging applications. Nat. Nanotechnol. 10, 924–936. 10.1038/nnano.2015.251 PubMed DOI

Zhu X., Su Q., Feng W., Li F. (2017). Anti-Stokes shift luminescent materials for bio-applications. Chem. Soc. Rev. 46, 1025–1039. 10.1039/C6CS00415F PubMed DOI

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