Highly complex nanoparticles combining multimodal imaging with the sensing of physical properties in biological systems can considerably enhance biomedical research, but reports demonstrating the performance of a single nanosized probe in several imaging modalities and its sensing potential at the same time are rather scarce. Gold nanoshells with magnetic cores and complex organic functionalization may offer an efficient multimodal platform for magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and fluorescence techniques combined with pH sensing by means of surface-enhanced Raman spectroscopy (SERS). In the present study, the synthesis of gold nanoshells with Mn-Zn ferrite cores is described, and their structure, composition, and fundamental properties are analyzed by powder X-ray diffraction, X-ray fluorescence spectroscopy, transmission electron microscopy, magnetic measurements, and UV-Vis spectroscopy. The gold surface is functionalized with four different model molecules, namely thioglycerol, meso-2,3-dimercaptosuccinate, 11-mercaptoundecanoate, and (11-mercaptoundecyl)-N,N,N-trimethylammonium bromide, to analyze the effect of varying charge and surface chemistry on cells in vitro. After characterization by dynamic and electrophoretic light scattering measurements, it is found that the particles do not exhibit significant cytotoxic effects, irrespective of the surface functionalization. Finally, the gold nanoshells are functionalized with a combination of 4-mercaptobenzoic acid and 7-mercapto-4-methylcoumarin, which introduces a SERS active pH sensor and a covalently attached fluorescent tag at the same time. 1H NMR relaxometry, fluorescence spectroscopy, and PAI demonstrate the multimodal potential of the suggested probe, including extraordinarily high transverse relaxivity, while the SERS study evidences a pH-dependent spectral response.

Center for Advanced Preclinical Imaging 1st Faculty of Medicine Charles University Salmovská 2 120 00 Prague Czech Republic

Department of Analytical Chemistry University of Chemistry and Technology Technická 5 166 28 Prague Czech Republic

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentská 573 532 10 Pardubice Czech Republic

Department of Medical Biochemistry Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

Faculty of Mathematics and Physics Charles University 5 Holešovičkách 2 180 00 Prague Czech Republic

Institute of Physics Czech Academy of Sciences Cukrovarnická 10 162 00 Prague Czech Republic

Zobrazit více v PubMed

Gleich B., Weizenecker R. Tomographic imaging using the nonlinear response of magnetic particles. Nature. 2005;435:1214–1217. doi: 10.1038/nature03808. PubMed DOI

Lee N., Yoo D., Ling D., Cho M.H., Hyeon T., Cheon J. Iron oxide based nanoparticles for multimodal imaging and magnetoresponsive therapy. Chem. Rev. 2015;115:10637–10689. doi: 10.1021/acs.chemrev.5b00112. PubMed DOI

Cui X.J., Mathe D., Kovacs N., Horvath I., Jauregui-Osoro M., de Rosales R.T.M., Mullen G.E.D., Wong W., Yan Y., Kruger D., et al. Synthesis, Characterization, and application of core shell Co0.16Fe2.84O4@NaYF4(Yb, Er) and Fe3O4@NaYF4(Yb, Tm) nanoparticle as trimodal (MRI, PET/SPECT, and Optical) imaging agents. Bioconjug. Chem. 2016;27:319–328. doi: 10.1021/acs.bioconjchem.5b00338. PubMed DOI PMC

Xing H.Y., Bu W.B., Zhang S.J., Zheng X.P., Li M., Chen F., He Q.J., Zhou L.P., Peng W.J., Hua Y.Q., et al. Mul-tifunctional nanoprobes for upconversion fluorescence, MR and CT trimodal imaging. Biomaterials. 2012;33:1079–1089. doi: 10.1016/j.biomaterials.2011.10.039. PubMed DOI

Song G.S., Zheng X.C., Wang Y.J., Xia X., Chu S., Rao J.H. A Magneto-optical nanoplatform for multimodality imaging of tumors in mice. ACS Nano. 2019;13:7750–7758. doi: 10.1021/acsnano.9b01436. PubMed DOI

Tomitaka A., Arami H., Ahmadivand A., Pala N., McGoron A.J., Takemura Y., Febo M., Nair M. Magneto-plasmonic nanostars for image-guided and NIR-triggered drug delivery. Sci. Rep. 2020;10:1–10. doi: 10.1038/s41598-020-66706-2. PubMed DOI PMC

Song G.S., Kenney M., Chen Y.S., Zheng X.C., Deng Y., Chen Z., Wang S.X., Gambhir S.S., Dai H.J., Rao J.H. Carbon-coated FeCo nanoparticles as sensitive magnetic-particle-imaging tracers with photothermal and magnetothermal properties. Nat. Biomed. Eng. 2020;4:325–334. doi: 10.1038/s41551-019-0506-0. PubMed DOI PMC

Wang M.L., Yang Q.M., Li M., Zou H.M., Wang Z.G., Ran H.T., Zheng Y.Y., Jian J., Zhou Y., Luo Y.D., et al. Multifunctional nanoparticles for multimodal imaging-guided low-intensity focused ultrasound/immunosynergistic retinoblastoma therapy. ACS Appl. Mater. Interfaces. 2020;12:5642–5657. doi: 10.1021/acsami.9b22072. PubMed DOI

Wang L.V. Multiscale photoacoustic microscopy and computed tomography. Nat. Photonics. 2009;3:503–509. doi: 10.1038/nphoton.2009.157. PubMed DOI PMC

Fu Q.R., Zhu R., Song J.B., Yang H.H., Chen X.Y. Photoacoustic imaging: Contrast agents and their biomedical applications. Adv. Mater. 2019;31:e1805875. doi: 10.1002/adma.201805875. PubMed DOI

Kneipp J., Kneipp H., Wittig B., Kneipp K. Following the dynamics of pH in endosomes of live cells with SERS nanosensors. J. Phys. Chem. C. 2010;114:7421–7426. doi: 10.1021/jp910034z. DOI

Kneipp J., Drescher D. Frontiers of Surface-Enhanced Raman Scattering. John Wiley & Sons, Inc.; Hoboken, NJ, USA: 2014. SERS in Cells: From Concepts to Practical Applications; pp. 285–308.

Bando K., Zhang Z., Graham D., Faulds K., Fujita K., Kawata S. Dynamic pH measurements of intracellular pathways using nano-plasmonic assemblies. Analyst. 2020;145:5768–5775. doi: 10.1039/D0AN00986E. PubMed DOI

Matsumoto Y., Jasanoff A. T-2 relaxation induced by clusters of superparamagnetic nanoparticles: Monte Carlo simulations. Magn. Reson. Imaging. 2008;26:994–998. doi: 10.1016/j.mri.2008.01.039. PubMed DOI

Dědourková T., Kaman O., Veverka P., Koktan J., Veverka M., Kuličková J., Jirák Z., Herynek V. Clusters of magnetic nanoparticles as contrast agents for MRI: The effect of aggregation on transverse relaxivity. IEEE Trans. Magn. 2015;51:5300804. doi: 10.1109/TMAG.2015.2438112. DOI

Kaman O., Kuličková J., Herynek V., Koktan J., Maryško M., Dědourková T., Knížek K., Jirák Z. Preparation of Mn-Zn ferrite nanoparticles and their silica-coated clusters: Magnetic properties and transverse relaxivity. J. Magn. Magn. Mater. 2017;427:251–257. doi: 10.1016/j.jmmm.2016.10.095. DOI

Kaman O., Kubániová D., Knížek K., Kubíčková L., Klementová M., Kohout J., Jirák Z. Structure and magnetic state of hydrothermally prepared Mn-Zn ferrite nanoparticles. J. Alloys Compd. 2021;888:161471. doi: 10.1016/j.jallcom.2021.161471. DOI

Salgueirino-Maceira V., Correa-Duarte M.A., Farle M., Lopez-Quintela A., Sieradzki K., Diaz R. Bifunctional gold-coated magnetic silica spheres. Chem. Mater. 2006;18:2701–2706. doi: 10.1021/cm0603001. DOI

Kaman O., Kuličková J., Maryško M., Veverka P., Herynek V., Havelek R., Královec K., Kubániová D., Kohout J., Dvořák P., et al. Mn-Zn ferrite nanoparticles with silica and titania coatings: Synthesis, transverse relaxivity and cytotoxicity. IEEE Trans. Magn. 2017;53:5300908. doi: 10.1109/TMAG.2017.2721365. DOI

Decher G. Fuzzy nanoassemblies: Toward layered polymeric multicomposites. Science. 1997;277:1232–1237. doi: 10.1126/science.277.5330.1232. DOI

Duff D.G., Baiker A., Edwards P.P. A new hydrosol of gold clusters. 1. Formation and particle-size variation. Langmuir. 1993;9:2301–2309. doi: 10.1021/la00033a010. DOI

Koktan J., Královec K., Havelek R., Kuličková J., Řezanka P., Kaman O. Magnetic oxide particles with gold nanoshells: Synthesis, properties and cytotoxic effects. Colloids Surf. A Physicochem. Eng. Asp. 2017;520:922–932. doi: 10.1016/j.colsurfa.2017.02.052. DOI

Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Xing J.Z., Zhu L., Jackson J.A., Gabos S., Sun X.-J., Wang X.-b., Xu X. Dynamic monitoring of cytotoxicity on microelectronic sensors. Chem. Res. Toxicol. 2005;18:154–161. doi: 10.1021/tx049721s. PubMed DOI

Xing J.Z., Zhu L., Gabos S., Xie L. Microelectronic cell sensor assay for detection of cytotoxicity and prediction of acute toxicity. Toxicol. In Vitro. 2006;20:995–1004. doi: 10.1016/j.tiv.2005.12.008. PubMed DOI

Straumanis M.E. Neubestimmung der gitterparameter, dichten und thermischen ausdehnungskoeffizienten von silber und gold, und vollkommenheit der struktur. Monatshefte Chem. Chem. Mon. 1971;102:1377–1386. doi: 10.1007/BF00917194. DOI

Ashayer R., Mannan S.H., Sajjadi S. Synthesis and characterization of gold nanoshells using poly (diallyldimethyl ammonium chloride) Colloids Surf. A Physicochem. Eng. Asp. 2008;329:134–141. doi: 10.1016/j.colsurfa.2008.07.004. DOI

Kaman O., Herynek V., Veverka P., Kubickova L., Pashchenko M., Kulickova J., Jirak Z. Transverse relaxivity of nanoparticle contrast agents for MRI: Different magnetic cores and coatings. IEEE Trans. Magn. 2018;54:1–5. doi: 10.1109/TMAG.2018.2844253. DOI

Kaman O., Kořínková T., Jirák Z., Maryško M., Veverka M. The superspin glass transition in zinc ferrite nanoparticles. J. Appl. Phys. 2015;117:17C706. doi: 10.1063/1.4907232. DOI

Lanterna A.E., González-Béjar M., Frenette M., Scaiano J.C. Photophysics of 7-mercapto-4-methylcoumarin and derivatives: Complementary fluorescence behaviour to 7-hydroxycoumarins. Photochem. Photobiol. Sci. 2017;16:1284–1289. doi: 10.1039/C7PP00121E. PubMed DOI

Yablonskiy D.A., Haacke E.M. Theory of NMR signal behavior in magnetically inhomogeneous tissues: The static dephasing regime. Magn. Reson. Med. 1994;32:749–763. doi: 10.1002/mrm.1910320610. PubMed DOI

Carroll M.R.J., Woodward R.C., House M.J., Teoh W.Y., Amal R., Hanley T.L., St Pierre T.G. Experimental validation of proton transverse relaxivity models for superparamagnetic nanoparticle MRI contrast agents. Nanotechnology. 2010;21:035103. doi: 10.1088/0957-4484/21/3/035103. PubMed DOI

Holz M., Heil S.R., Sacco A. Temperature-dependent self-diffusion coefficients of water and six selected molecular liquids for calibration in accurate 1H NMR PFG measurements. Phys. Chem. Chem. Phys. 2000;2:4740–4742. doi: 10.1039/b005319h. DOI

Weber V., Feis A., Gellini C., Pilot R., Salvi P.R., Signorini R. Far- and near-field properties of gold nanoshells studied by photoacoustic and surface-enhanced Raman spectroscopies. Phys. Chem. Chem. Phys. 2015;17:21190–21197. doi: 10.1039/C4CP05054A. PubMed DOI

Oldenburg S.J., Averitt R.D., Westcott S.L., Halas N.J. Nanoengineering of optical resonances. Chem. Phys. Lett. 1998;288:243–247. doi: 10.1016/S0009-2614(98)00277-2. DOI

Jain P.K., Lee K.S., El-Sayed I.H., El-Sayed M.A. Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: Applications in biological imaging and biomedicine. J. Phys. Chem. B. 2006;110:7238–7248. doi: 10.1021/jp057170o. PubMed DOI

Link S., El-Sayed M.A. Size and temperature dependence of the plasmon absorption of colloidal gold nanoparticles. J. Phys. Chem. B. 1999;103:4212–4217. doi: 10.1021/jp984796o. DOI

Ni W.H., Kou X., Yang Z., Wang J.F. Tailoring longitudinal surface plasmon wavelengths, scattering and absorption cross sections of gold nanorods. ACS Nano. 2008;2:677–686. doi: 10.1021/nn7003603. PubMed DOI

Michota A., Bukowska J. Surface-enhanced Raman scattering (SERS) of 4-mercaptobenzoic acid on silver and gold substrates. J. Raman Spectrosc. 2003;34:21–25. doi: 10.1002/jrs.928. DOI

Vogel E., Gbureck A., Kiefer W. Vibrational spectroscopic studies on the dyes cresyl violet and coumarin 152. J. Mol. Struct. 2000;550:177–190. doi: 10.1016/S0022-2860(00)00385-9. DOI

Bassi B., Taglietti A., Galinetto P., Marchesi N., Pascale A., Cabrini E., Pallavicini P., Dacarro G. Tunable coating of gold nanostars: Tailoring robust SERS labels for cell imaging. Nanotechnology. 2016;27:265302. doi: 10.1088/0957-4484/27/26/265302. PubMed DOI

Vogel E., Kiefer W. Investigation of the metal adsorbate interface of the system silver coumarin and silver hydrocoumarin by means of surface enhanced Raman spectroscopy. Fresenius J. Anal. Chem. 1998;361:628–630. doi: 10.1007/s002160050972. DOI