Abstract
The difficulty in delineating tumor is a major obstacle for better outcomes in cancer treatment of patients. The use of single-imaging modality is often limited by inadequate sensitivity and resolution. Here, we present the synthesis and the use of monodisperse iron oxide nanoparticles coated with fluorescent silica nano-shells for fluorescence and magnetic resonance dual imaging of tumor. The as-synthesized core–shell nanoparticles were designed to improve the accuracy of diagnosis via simultaneous tumor imaging with dual imaging modalities by a single injection of contrast agent. The iron oxide nanocrystals (~11 nm) were coated with Rhodamine B isothiocyanate-doped silica shells via reverse microemulsion method. Then, the core–shell nanoparticles (~54 nm) were analyzed to confirm their size distribution by transmission electron microscopy and dynamic laser scattering. Photoluminescence spectroscopy was used to characterize the fluorescent property of the dye-doped silica shell-coated nanoparticles. The cellular compatibility of the as-prepared nanoparticles was confirmed by a trypan blue dye exclusion assay and the potential as a dual-imaging contrast agent was verified by in vivo fluorescence and magnetic resonance imaging. The experimental results show that the uniform-sized core–shell nanoparticles are highly water dispersible and the cellular toxicity of the nanoparticles is negligible. In vivo fluorescence imaging demonstrates the capability of the developed nanoparticles to selectively target tumors by the enhanced permeability and retention effects and ex vivo tissue analysis was corroborated this. Through in vitro phantom test, the core/shell nanoparticles showed a T2 relaxation time comparable to Feridex® with smaller size, indicating that the as-made nanoparticles are suitable for imaging tumor. This new dual-modality-nanoparticle approach has promised for enabling more accurate tumor imaging.
Graphical Abstract
Similar content being viewed by others
References
Bakalova R, Zhelev Z, Aoki I, Masamoto K, Mileva M, Obata T, Higuchi M, Gadjeva V, Kanno I (2008) Multimodal silica-shelled quantum dots: direct intracellular delivery, photosensitization, toxic, and microcirculation effects. Bioconjug Chem 19:1135–1142. doi:10.1021/bc700431c
Benezra M, Penate-Medina O, Zanzonico PB, Schaer D, Ow H, Burns A, DeStanchina E, Longo V, Herz E, Iyer S, Wolchok J, Larson SM, Wiesner U, Bradbury MS (2011) Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J Clin Investig 121:2768–2780. doi:10.1172/JCI45600
Bumb A, Brechbiel M, Choyke P, Fugger L, Eggeman A, Prabhakaran D, Hutchinson J, Dobson PJ (2008) Synthesis and characterization of ultra-small superparamagnetic iron oxide nanoparticles thinly coated with silica. Nanotechnology 19:335601. doi:10.1088/0957-4484/19/33/335601
Bumb A, Regino CA, Perkins MR, Bernardo M, Ogawa M, Fugger L, Choyke PL, Dobson PJ, Brechbiel MW (2010) Preparation and characterization of a magnetic and optical dual-modality molecular probe. Nanotechnology 21:175704. doi:10.1088/0957-4484/21/17/175704
Burns A, Ow H, Wiesner U (2006) Fluorescent core–shell silica nanoparticles: towards “Lab on a Particle” architectures for nanobiotechnology. Chem Soc Rev 35:1028–1042. doi:10.1039/B600562B
Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM (2009) Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 29:1433–1449. doi:10.1148/rg.295095034
Chinen AB, Guan CM, Ferrer JR, Barnaby SN, Merkel TJ, Mirkin CA (2015) Nanoparticle probes for the detection of cancer biomarkers, cells, and tissues by fluorescence. Chem Rev. doi:10.1021/acs.chemrev.5b00321
Cho K, Wang X, Nie S, Chen ZG, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14:1310–1316. doi:10.1158/1078-0432.CCR-07-1441
Ding H, Zhang Y, Wang S, Xu J, Xu S, Li G (2012) Fe3O4@SiO2 core/shell nanoparticles: the silica coating regulations with a single core for different core sizes and shell thicknesses. Chem Mater. doi:10.1021/cm302828d
Hu F, Joshi HM, Dravid VP, Meade TJ (2010) High-performance nanostructured MR contrast probes. Nanoscale 2:1884–1891. doi:10.1039/c0nr00173b
Hu F, Jia Q, Li Y, Gao M (2011) Facile synthesis of ultrasmall PEGylated iron oxide nanoparticles for dual-contrast T1-and T2-weighted magnetic resonance imaging. Nanotechnology 22:245604. doi:10.1088/0957-4484/22/24/245604
Hyeon T, Lee SS, Park J, Chung Y, Na HB (2001) Synthesis of highly crystalline and monodisperse maghemite nanocrystallites without a size-selection process. J Am Chem Soc 123:12798–12801. doi:10.1021/ja016812s
Jang ES, Lee SY, Cha EJ, Sun IC, Kwon IC, Kim D, Kim YI, Kim K, Ahn CH (2014) Fluorescent dye labeled iron oxide/silica core/shell nanoparticle as a multimodal imaging probe. Pharm Res 31:3371–3378. doi:10.1007/s11095-014-1426-z
Jiang F, Fu Y, Zhu Y, Tang Z, Sheng P (2012) Fabrication of iron oxide/silica core–shell nanoparticles and their magnetic characteristics. J Alloys Compd 543:43–48. doi:10.1016/j.jallcom.2012.07.079
Jun YW, Huh YM, Choi JS, Lee JH, Song HT, Kim S, Kim S, Yoon S, Kim KS, Shin JS, Sun JS, Cheon J (2005) Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging. J Am Chem Soc 127:5732–5733. doi:10.1021/ja0422155
Jung H, Park B, Lee C, Cho J, Suh J, Park J, Kim Y, Kim J, Cho G, Dual Cho H (2014) MRI T1 and T2(*) contrast with size-controlled iron oxide nanoparticles. Nanomedicine 10:1679–1689. doi:10.1016/j.nano.2014.05.003
Junttila MR, de Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501:346–354. doi:10.1038/nature12626
Kim BH, Lee N, Kim H, An K, Park YI, Choi Y, Shin K, Lee Y, Kwon SG, Na HB, Park JG, Ahn TY, Kim YW, Moon WK, Choi SH, Hyeon T (2011) Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T1 magnetic resonance imaging contrast agents. J Am Chem Soc 133:12624–12631. doi:10.1021/ja203340u
Kim T, Lee N, Park YI, Kim J, Kim J, Lee EY, Yi M, Ki BG, Hyeon T, Yu T, Na HB (2014) Mesoporous silica-coated luminescent Eu3+ doped GdVO4 nanoparticles for multimodal imaging and drug delivery. RSC Adv 4:45687–45695. doi:10.1039/C4RA06628F
Ladj R, Bitar A, Eissa M, Mugnier Y, Le Dantec R, Fessi H, Elaissari A (2013) Individual inorganic nanoparticles: preparation, functionalization and in vitro biomedical diagnostic applications. J Mater Chem B 1:1381–1396. doi:10.1039/C2TB00301E
Larson DR, Ow H, Vishwasrao HD, Heikal AA, Wiesner U, Webb WW (2008) Silica nanoparticle architecture determines radiative properties of encapsulated fluorophores. Chem Mater 20:2677–2684. doi:10.1021/cm7026866
Lee N, Hyeon T (2012) Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem Soc Rev 41:2575–2589. doi:10.1039/C1CS15248C
Lee JH, Huh YM, Jun YW, Seo JW, Jang JT, Song HT, Kim S, Cho EJ, Yoon HG, Suh JS, Cheon J (2007) Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging. Nat Med 13:95–99. doi:10.1038/nm1467
Lee DE, Koo H, Sun IC, Ryu JH, Kim K, Kwon IC (2012a) Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev 41:2656–2672. doi:10.1039/C2CS15261D
Lee N, Cho HR, Oh MH, Lee SH, Kim K, Kim BH, Shin K, Ahn TY, Choi JW, Kim YW, Choi SH, Hyeon T (2012b) Multifunctional Fe3O4/TaOx core/shell nanoparticles for simultaneous magnetic resonance imaging and X-ray computed tomography. J Am Chem Soc 134:10309–10312. doi:10.1021/ja3016582
Liong M, Lu J, Kovochich M, Xia T, Ruehm SG, Nel AE, Tamanoi F, Zink JI (2008) Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano 2:889–896. doi:10.1021/nn800072t
Mohan Kant K, Sethupathi K, Ramachandra Rao MS (2008) Tuning the magnetization dynamics of silica-coated Fe3O4 core–shell nanoparticles by shell thickness control. J Appl Phys 103:07D501–07D501-3
Na HB, Palui G, Rosenberg JT, Ji X, Grant SC, Mattoussi H (2012) Multidentate catechol-based polyethylene glycol oligomers provide enhanced stability and biocompatibility to iron oxide nanoparticles. ACS Nano 6:389–399. doi:10.1021/nn203735b
Ow H, Larson DR, Srivastava M, Baird BA, Webb WW, Wiesner U (2005) Bright and stable core–shell fluorescent silica nanoparticles. Nano Lett 5:113–117. doi:10.1021/nl0482478
Park J, An K, Hwang Y, Park JG, Noh HJ, Kim JY, Park JH, Hwang NM, Hyeon T (2004) Ultra-large-scale syntheses of monodisperse nanocrystals. Nat Mater 3:891–895. doi:10.1038/nmat1251
Piao Y, Burns A, Kim J, Wiesner U, Hyeon T (2008) Designed fabrication of silica-based nanostructured particle systems for nanomedicine applications. Adv Funct Mater 18:3745–3758. doi:10.1002/adfm.200800731
Shi D, Sadat M, Dunn AW, Mast DB (2015) Photo-fluorescent and magnetic properties of iron oxide nanoparticles for biomedical applications. Nanoscale 7:8209–8232. doi:10.1039/C5NR01538C
Sun S, Zeng H (2002) Size-controlled synthesis of magnetite nanoparticles. J Am Chem Soc 124:8204–8205. doi:10.1021/ja026501x
Sun S, Zeng H, Robinson DB, Raoux S, Rice PM, Wang SX, Li G (2004) Monodisperse MFe2O4 (M = Fe Co, Mn) nanoparticles. J Am Chem Soc 126:273–279. doi:10.1021/ja0380852
Thorek DL, Ulmert D, Diop NF, Lupu ME, Doran MG, Huang R, Abou DS, Larson SM, Grimm J (2014) Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle. Nat Commun 5:3097. doi:10.1038/ncomms4097
Tromsdorf UI, Bigall NC, Kaul MG, Bruns OT, Nikolic MS, Mollwitz B, Sperling RA, Reimer R, Hohenberg H, Parak WJ, Förster S, Beisiegel U, Adam G, Weller H (2007) Size and surface effects on the MRI relaxivity of manganese ferrite nanoparticle contrast agents. Nano Lett 7:2422–2427. doi:10.1021/nl071099b
Yang KM, Cho HI, Choi HJ, Piao Y (2014) Synthesis of water well-dispersed PEGylated iron oxide nanoparticles for MR/optical lymph node imaging. J Mater Chem B 2:3355–3364. doi:10.1039/C4TB00084F
Ye F, Laurent S, Fornara A, Astolfi L, Qin J, Roch A, Martini A, Toprak MS, Muller RN, Muhammed M (2012) Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T2 contrast agent with tunable proton relaxivities. Contrast Media Mol Imaging 7:460–468. doi:10.1002/cmmi.1473
Yi DK, Lee SS, Papaefthymiou GC, Ying JY (2006) Nanoparticle architectures templated by SiO2/Fe2O3 nanocomposites. Chem Mater 18:614–619. doi:10.1021/cm0512979
Zhang M, Cushing BL, O’Connor CJ (2008) Synthesis and characterization of monodisperse ultra-thin silica-coated magnetic nanoparticles. Nanotechnology 19:085601. doi:10.1088/0957-4484/19/8/085601
Acknowledgments
This work was supported by Nano Material Technology Development Program (NRF-2015M3A7B6027970) of MSIP/NRF and by the Center for Integrated Smart Sensors funded by the Ministry of Science, ICT and Future Planning, Republic of Korea, as Global Frontier Project (CISS-012M3A6A6054186). The authors gratefully acknowledge technical support from Biomedical Imaging Infrastructure, Department of Radiology, Asan Medical Center. The authors also thank Mr. Juhwan Yoon, Mr. Min Su Kang, Ms. Ga Ram Kim, Ms. So Jeong Kim, Mr. Wan Kim, and Mr. Jong Ahn Lee for assistance with the fluorescence imaging experiments.
Author information
Authors and Affiliations
Corresponding author
Additional information
Haeyun Jang and Chaedong Lee have contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Jang, H., Lee, C., Nam, GE. et al. In vivo magnetic resonance and fluorescence dual imaging of tumor sites by using dye-doped silica-coated iron oxide nanoparticles. J Nanopart Res 18, 41 (2016). https://doi.org/10.1007/s11051-016-3353-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11051-016-3353-x