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EJNMMI Research
Published in: EJNMMI Research 1/2020

01-12-2020 | Magnetic Resonance Imaging | Original research

Simultaneous in vivo PET/MRI using fluorine-18 labeled Fe3O4@Al(OH)3 nanoparticles: comparison of nanoparticle and nanoparticle-labeled stem cell distribution

Authors: Sarah Belderbos, Manuel Antonio González-Gómez, Frederik Cleeren, Jens Wouters, Yolanda Piñeiro, Christophe M. Deroose, An Coosemans, Willy Gsell, Guy Bormans, Jose Rivas, Uwe Himmelreich

Published in: EJNMMI Research | Issue 1/2020

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Abstract

Background

Mesenchymal stem cells (MSCs) have shown potential for treatment of different diseases. However, their working mechanism is still unknown. To elucidate this, the non-invasive and longitudinal tracking of MSCs would be beneficial. Both iron oxide-based nanoparticles (Fe3O4 NPs) for magnetic resonance imaging (MRI) and radiotracers for positron emission tomography (PET) have shown potential as in vivo cell imaging agents. However, they are limited by their negative contrast and lack of spatial information as well as short half-life, respectively. In this proof-of-principle study, we evaluated the potential of Fe3O4@Al(OH)3 NPs as dual PET/MRI contrast agents, as they allow stable binding of [18F]F− ions to the NPs and thus, NP visualization and quantification with both imaging modalities.

Results

18F-labeled Fe3O4@Al(OH)3 NPs (radiolabeled NPs) or mouse MSCs (mMSCs) labeled with these radiolabeled NPs were intravenously injected in healthy C57Bl/6 mice, and their biodistribution was studied using simultaneous PET/MRI acquisition. While liver uptake of radiolabeled NPs was seen with both PET and MRI, mMSCs uptake in the lungs could only be observed with PET. Even some initial loss of fluoride label did not impair NPs/mMSCs visualization. Furthermore, no negative effects on blood cell populations were seen after injection of either the NPs or mMSCs, indicating good biocompatibility.

Conclusion

We present the application of novel 18F-labeled Fe3O4@Al(OH)3 NPs as safe cell tracking agents for simultaneous PET/MRI. Combining both modalities allows fast and easy NP and mMSC localization and quantification using PET at early time points, while MRI provides high-resolution, anatomic background information and long-term NP follow-up, hereby overcoming limitations of the individual imaging modalities.
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Literature
1.
Gregoire C, Briquet A, Pirenne C, Lechanteur C, Louis E, Beguin Y. Allogeneic mesenchymal stromal cells for refractory luminal Crohn’s disease: a phase I–II study. Dig Liver Dis. 2018;50:1251–5.PubMed
2.
Ma F, Li R, Tang H, Zhu T, Xu F, Zhu J. Regulation of autophagy in mesenchymal stem cells modulates therapeutic effects on spinal cord injury. Brain Res. 2019;1721:146321.PubMed
3.
Calonge M, Pérez I, Galindo S, Nieto-Miguel T, López-Paniagua M, Fernández I, et al. A proof-of-concept clinical trial using mesenchymal stem cells for the treatment of corneal epithelial stem cell deficiency. Transl Res. 2019;206:18–40.PubMed
4.
Satué M, Schüler C, Ginner N, Erben RG. Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci Rep. 2019;9:10153.PubMedPubMedCentral
5.
Hoogduijn MJ, Lombardo E. Mesenchymal stromal cells anno 2019: dawn of the therapeutic era? Concise Review. Stem Cells Transl Med. 2019;8:1126–34.
6.
Krueger TEG, Thorek DLJ, Denmeade SR, Isaacs JT, Brennen WN. Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem Cells Transl Med. 2018;7:651–63.PubMedPubMedCentral
7.
Serakinci N, Christensen R, Fahrioglu U, Sorensen FB, Dagnæs-Hansen F, Hajek M, et al. Mesenchymal stem cells as therapeutic delivery vehicles targeting tumor stroma. Cancer Biother Radiopharm. 2011;26:767–73.PubMed
8.
Kalamegam G, Memic A, Budd E, Abbas M, Mobasheri A. A comprehensive review of stem cells for cartilage regeneration in osteoarthritis. In: Turksen K (ed) Adv Exp Med Biol. Cham: Springer; 2018. p. 23–36.
9.
10.
Holvoet B, Quattrocelli M, Belderbos S, et al. Sodium iodide symporter PET and BLI noninvasively reveal mesoangioblast survival in dystrophic mice. Stem cell reports. 2015;5:1183–95.PubMedPubMedCentral
11.
Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande VG, et al. Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach. Stem Cell Res Ther. 2015;6:163.PubMedPubMedCentral
12.
Holvoet B, Leten C, Deroose CM, Himmelreich U. Noninvasive monitoring of suicide gene therapy by using multimodal molecular imaging. In: Methods Mol. Biol. New York: Springer New York; 2019. p. 123–34.
13.
Kim MH, Lee YJ, Kang JH. Stem cell monitoring with a direct or indirect labeling method. Nucl Med Mol Imaging (2010). 2016;50:275–83.
14.
Himmelreich U, Dresselaers T. Cell labeling and tracking for experimental models using magnetic resonance imaging. Methods. 2009;48:112–24.PubMed
15.
Srivastava AK, Bulte JWM. Seeing stem cells at work in vivo. Stem Cell Rev Reports. 2014;10:127–44.
16.
Tietze R, Zaloga J, Unterweger H, Lyer S, Friedrich RP, Janko C, et al. Magnetic nanoparticle-based drug delivery for cancer therapy. Biochem Biophys Res Commun. 2015;468:463–70.PubMed
17.
Luong TT, Knoppe S, Bloemen M, Brullot W, Strobbe R, Locquet J-P, et al. Magnetothermal release of payload from iron oxide/silica drug delivery agents. J Magn Magn Mater. 2016;416:194–9.
18.
Debbage P, Jaschke W. Molecular imaging with nanoparticles: giant roles for dwarf actors. Histochem Cell Biol. 2008;130:845–75.PubMed
19.
Terreno E, Castelli DD, Viale A, Aime S. Challenges for molecular magnetic resonance imaging. Chem Rev. 2010;110:3019–42.PubMed
20.
Wolfs E, Struys T, Notelaers T, et al. 18F-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for PET imaging: effects on ultrastructure and differentiation capacity. J Nucl Med. 2013;54:447–54.PubMed
21.
MacAskill MG, Tavares AS, Wu J, Lucatelli C, Mountford JC, Baker AH, et al. PET cell tracking using 18F-FLT is not limited by local reuptake of free radiotracer. Sci Rep. 2017;7:44233.PubMedPubMedCentral
22.
Lanfranca MP, Lazarus J, Shao X, Nathan H, Di Magliano MP, Zou W, et al. Tracking macrophage infiltration in a mouse model of pancreatic cancer with the positron emission tomography tracer [11C]PBR28. J Surg Res. 2018;232:570–7.PubMedPubMedCentral
23.
Neyrinck K, Breuls N, Holvoet B, et al. The human somatostatin receptor type 2 as an imaging and suicide reporter gene for pluripotent stem cell-derived therapy of myocardial infarction. Theranostics. 2018;8:2799–813.PubMedPubMedCentral
24.
Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–80.PubMed
25.
Kiani A, Esquevin A, Lepareur N, Bourguet P, Le Jeune F, Gauvrit J. Main applications of hybrid PET-MRI contrast agents: a review. Contrast Media Mol Imaging. 2016;11:92–8.PubMed
26.
Lahooti A, Sarkar S, Laurent S, Shanehsazzadeh S. Dual nano-sized contrast agents in PET/MRI: a systematic review. Contrast Media Mol Imaging. 2016;11:428–47.PubMed
27.
Abou DS, Thorek DLJ, Ramos NN, Pinkse MWH, Wolterbeek HT, Carlin SD, et al. 89Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer. Pharm Res. 2013;30:878–88.PubMed
28.
Xie J, Chen K, Huang J, Lee S, Wang J, Gao J, et al. PET/NIRF/MRI triple functional iron oxide nanoparticles. Biomaterials. 2010;31:3016–22.PubMedPubMedCentral
29.
Fernández-Barahona I, Muñoz-Hernando M, Pellico J, Ruiz-Cabello J, Herranz F. Molecular imaging with 68Ga radio-nanomaterials: shedding light on nanoparticles. Appl Sci. 2018;8:1098.
30.
Lee SB, Kumar D, Li Y, Lee I-K, Cho SJ, Kim SK, et al. PEGylated crushed gold shell-radiolabeled core nanoballs for in vivo tumor imaging with dual positron emission tomography and Cerenkov luminescent imaging. J Nanobiotechnology. 2018;16:41.PubMedPubMedCentral
31.
Cui X, Belo S, Krüger D, et al. Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging. Biomaterials. 2014;35:5840–6.PubMedPubMedCentral
32.
Thomas G, Boudon J, Maurizi L, et al. Innovative magnetic nanoparticles for PET/MRI bimodal imaging. ACS Omega. 2019;4:2637–48.PubMedPubMedCentral
33.
34.
Li L. The biochemistry and physiology of metallic fluoride: action, mechanism, and implications. Crit Rev Oral Biol Med. 2003;14:100–14.PubMed
35.
González-Gómez MA, Belderbos S, Yañez-Vilar S, Piñeiro Y, Cleeren F, Bormans G, et al. Development of superparamagnetic nanoparticles coated with polyacrylic acid and aluminum hydroxide as an efficient contrast agent for multimodal imaging. Nanomaterials. 2019;9:1626.PubMedCentral
36.
Leten C. Multi-modal small animal imaging of brain tumor therapy assessment. PhD Thesis. Leuven: KU Leuven; 2014.
37.
Park E-J, Oh SY, Kim Y, Yoon C, Lee B-S, Kim SD, et al. Distribution and immunotoxicity by intravenous injection of iron nanoparticles in a murine model. J Appl Toxicol. 2016;36:414–23.PubMed
38.
Park E-J, Lee G-H, Yoon C, Jeong U, Kim Y, Cho M-H, et al. Biodistribution and toxicity of spherical aluminum oxide nanoparticles. J Appl Toxicol. 2016;36:424–33.PubMed
39.
Cleeren F, Lecina J, Ahamed M, et al. Al18F-labeling of heat-sensitive biomolecules for positron emission tomography imaging. Theranostics. 2017;7:2924–39.PubMedPubMedCentral
40.
Thonon D, Goblet D, Goukens E, Kaisin G, Paris J, Aerts J, et al. Fully automated preparation and conjugation of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) with RGD peptide using a GE FASTlabTM synthesizer. Mol Imaging Biol. 2011;13:1088–95.PubMed
41.
Olberg DE, Arukwe JM, Grace D, Hjelstuen OK, Solbakken M, Kindberg GM, et al. One step radiosynthesis of 6-[18 F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([18F]F-Py-TFP): a new prosthetic group for efficient labeling of biomolecules with fluorine-18. J Med Chem. 2010;53:1732–40.PubMed
42.
Stéen EJL, Edem PE, Nørregaard K, Jørgensen JT, Shalgunov V, Kjaer A, et al. Pretargeting in nuclear imaging and radionuclide therapy: improving efficacy of theranostics and nanomedicines. Biomaterials. 2018;179:209–45.PubMed
43.
Billaud EMF, Belderbos S, Cleeren F, Maes W, Van de Wouwer M, Koole M, et al. Pretargeted PET imaging using a bioorthogonal 18F-labeled trans-cyclooctene in an ovarian carcinoma model. Bioconjug Chem. 2017;28:2915–20.PubMed
44.
Sun Y, Yu M, Liang S, et al. Fluorine-18 labeled rare-earth nanoparticles for positron emission tomography (PET) imaging of sentinel lymph node. Biomaterials. 2011;32:2999–3007.PubMed
45.
Keliher EJ, Yoo J, Nahrendorf M, Lewis JS, Marinelli B, Newton A, et al. 89 Zr-labeled dextran nanoparticles allow in vivo macrophage imaging. Bioconjug Chem. 2011;22:2383–9.PubMedPubMedCentral
46.
Wilks M, Reeves P, Yuan H, Kools F, Takahashi K, Kaittanis C, et al. In vivo PET imaging of T-cell trafficking by 89Zr-radiolabeled nanoparticles; 2017. Society of Nuclear Medicine.
47.
Wilks M, Albrecht D, Yuan H, El Fakhri G, Brugarolas P, Normandin M. 89Zr-nanoparticle based PET imaging of B-cell trafficking in a murine model of multiple sclerosis. In: J. Nucl. Med. Society of nuclear medicine; 2018. p. 264.
48.
Hinds KA, Hill JM, Shapiro EM, Laukkanen MO, Silva AC, Combs CA, et al. Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. Blood. 2003;102:867–72.PubMed
49.
Heyn C, Ronald JA, Ramadan SS, et al. In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med. 2006;56:1001–10.PubMed
50.
Struys T, Ketkar-Atre A, Gervois P, et al. Magnetic resonance imaging of human dental pulp stem cells in vitro and in vivo. Cell Transplant. 2013;22:1813–29.PubMed
51.
Garcia Ribeiro RS, Gysemans C, da Cunha JPMCM, et al. Magnetoliposomes as contrast agents for longitudinal in vivo assessment of transplanted pancreatic islets in a diabetic rat model. Sci Rep. 2018;8:11487.PubMedPubMedCentral
52.
Himmelreich U, Hoehn M. Stem cell labeling for magnetic resonance imaging. Minim Invasive Ther Allied Technol. 2008;17:132–42.PubMed
53.
54.
Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.PubMedPubMedCentral
55.
Lu W, Fu C, Song L, Yao Y, Zhang X, Chen Z, et al. Exposure to supernatants of macrophages that phagocytized dead mesenchymal stem cells improves hypoxic cardiomyocytes survival. Int J Cardiol. 2013;165:333–40.PubMed
56.
Wang H, Sebrié C, Ruaud J-P, Guillot G, Bouazizi-Verdier K, Willoquet G, et al. Aerosol deposition in the lungs of spontaneously breathing rats using Gd-DOTA-based contrast agents and ultra-short echo time MRI at 1.5 tesla. Magn Reson Med. 2016;75:594–605.PubMed
57.
Hong W, He Q, Fan S, Carl M, Shao H, Chen J, et al. Imaging and quantification of iron-oxide nanoparticles (IONP) using MP-RAGE and UTE based sequences. Magn Reson Med. 2017;78:226–32.PubMed
58.
Jadvar H, Desai B, Conti PS. Sodium 18F-fluoride PET/CT of bone, joint, and other disorders. Semin Nucl Med. 2015;45:58–65.PubMedPubMedCentral
59.
Cleeren F, Lecina J, Billaud EMF, Ahamed M, Verbruggen A, Bormans GM. New chelators for low temperature Al 18 F-labeling of biomolecules. Bioconjug Chem. 2016;27:790–8.PubMed
60.
Elsasser-Beile U, Reischl G, Wiehr S, Buhler P, Wolf P, Alt K, et al. PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen. J Nucl Med. 2009;50:606–11.PubMed
61.
Rolle A-M, Hasenberg M, Thornton CR, et al. ImmunoPET/MR imaging allows specific detection of aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci. 2016;113:E1026–33.PubMed
62.
Manshian BB, Munck S, Agostinis P, Himmelreich U, Soenen SJ. High content analysis at single cell level identifies different cellular responses dependent on nanomaterial concentrations. Sci Rep. 2015;5:13890.PubMedPubMedCentral
Metadata
Title
Simultaneous in vivo PET/MRI using fluorine-18 labeled Fe3O4@Al(OH)3 nanoparticles: comparison of nanoparticle and nanoparticle-labeled stem cell distribution
Authors
Sarah Belderbos
Manuel Antonio González-Gómez
Frederik Cleeren
Jens Wouters
Yolanda Piñeiro
Christophe M. Deroose
An Coosemans
Willy Gsell
Guy Bormans
Jose Rivas
Uwe Himmelreich
Publication date
01-12-2020
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-020-00655-9

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