19F magnetic resonance (19F MR) tracers stand out for their wide range of applications in experimental and clinical medicine, as they can be precisely located in living tissues with negligible fluorine background. This contribution demonstrates the long-term dissolution of multiresponsive fluorinated implants designed for prolonged release. Implants were detected for 14 (intramuscular injection) and 20 (subcutaneous injection) months by 19F MR at 4.7 T, showing favorable MR relaxation times, biochemical stability, biological compatibility and slow, long-term dissolution. Thus, polymeric implants may become a platform for long-term local theranostics.

Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Hlavova 8 Prague 128 00 Czech Republic

Faculty of Health Studies Technical University of Liberec Studentska 1402 2 Liberec 461 17 Czech Republic

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Katerinska 1660 32 Prague 121 08 Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovsky square 2 162 06 Prague Czech Republic

Radiodiagnostic and Interventional Radiology Department Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic 420 736467349

Zobrazit více v PubMed

Rogosnitzky M. Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. BioMetals. 2016;29:365–376. doi: 10.1007/s10534-016-9931-7. doi: 10.1007/s10534-016-9931-7. PubMed DOI PMC

Kostiv U. Natile M. M. Jirák D. Půlpánová D. Jiráková K. Vosmanská M. et al., Peg-neridronate-modified NaYf4:GD3+,Yb3+,TM3+/NaGdf4 core–shell upconverting nanoparticles for bimodal magnetic resonance/optical luminescence imaging. ACS Omega. 2021;6:14420–14429. doi: 10.1021/acsomega.1c01313. doi: 10.1021/acsomega.1c01313. PubMed DOI PMC

Ziółkowska N. Vít M. Laga R. Jirák D. Iron-doped calcium phytate nanoparticles as a bio-responsive contrast agent in 1H/31P magnetic resonance imaging. Sci. Rep. 2022;12(1):2118. doi: 10.1038/s41598-022-06125-7. doi: 10.1038/s41598-022-06125-7. PubMed DOI PMC

Kracíková L. Ziółkowska N. Androvič L. Klimánková I. Červený D. Vít M. et al., Phosphorus-containing Polymeric Zwitterion: a pioneering bioresponsive probe for 31 p-magnetic resonance imaging. Macromol. Biosci. 2022:2100523. doi: 10.1002/mabi.202100523. doi: 10.1002/mabi.202100523. PubMed DOI

Brus J. Urbanova M. Sedenkova I. Brusova H. New Perspectives of 19F MAS NMR in the characterization of amorphous forms of atorvastatin in dosage formulations. Int. J. Pharm. 2011;409:62–74. doi: 10.1016/j.ijpharm.2011.02.030. doi: 10.1016/j.ijpharm.2011.02.030. PubMed DOI

Sedlacek O. Jirak D. Vit M. Ziołkowska N. Janouskova O. Hoogenboom R. Fluorinated water-soluble poly(2-oxazoline)s as highly sensitive 19F MRI contrast agents. Macromolecules. 2020;53:6387–6395. doi: 10.1021/acs.macromol.0c01228. doi: 10.1021/acs.macromol.0c01228. DOI

Kolouchova K. Jirak D. Groborz O. Sedlacek O. Ziolkowska N. Vit M. et al., Implant-forming polymeric 19f MRI-tracer with tunable dissolution. JCR. 2020;327:50–60. doi: 10.1016/j.jconrel.2020.07.026. PubMed DOI

Jirak D. Galisova A. Kolouchova K. Babuka D. Hruby M. Fluorine polymer probes for Magnetic Resonance Imaging: Quo Vadis?, Magnetic Resonance Materials in Physics. Biol. Med. 2018;32:173–185. doi: 10.1007/s10334-018-0724-6. PubMed DOI PMC

Rolfe B. E. Blakey I. Squires O. Peng H. Boase N. R. Alexander C. et al., Multimodal polymer nanoparticles with combined 19F magnetic resonance and optical detection for tunable, targeted, multimodal imaging in vivo. J. Am. Chem. Soc. 2014;136:2413–2419. doi: 10.1021/ja410351h. doi: 10.1021/ja410351h. PubMed DOI

Ahrens E. T. Helfer B. M. O'Hanlon C. F. Schirda C. Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19 MRI. Magn. Reson. Med. 2014;72:1696–1701. doi: 10.1002/mrm.25454. doi: 10.1002/mrm.25454. PubMed DOI PMC

Kaberov L. I. Kaberova Z. Murmiliuk A. Trousil J. Sedláček O. Konefal R. et al., Fluorine-containing block and gradient copoly(2-oxazoline)s based on 2-(3,3,3-trifluoropropyl)-2-oxazoline: a quest for the optimal self-assembled structure for 19F imaging. Biomacromolecules. 2021;22:2963–2975. doi: 10.1021/acs.biomac.1c00367. doi: 10.1021/acs.biomac.1c00367. PubMed DOI

Jirak D. Svoboda J. Filipová M. Pop-Georgievski O. Sedlacek O. Antifouling fluoropolymer-coated nanomaterials for 19F MRI. Chem. Commun. 2021;57:4718–4721. doi: 10.1039/d1cc00642h. doi: 10.1039/D1CC00642H. PubMed DOI

Fink C. Gaudet J. M. Fox M. S. Bhatt S. Viswanathan S. Smith M. et al., 19F-perfluorocarbon-labeled human peripheral blood mononuclear cells can be detected in vivo using clinical MRI parameters in a therapeutic cell setting. Sci. Rep. 2018;8(1):590. doi: 10.1038/s41598-017-19031-0. doi: 10.1038/s41598-017-19031-0. PubMed DOI PMC

Vít M. Burian M. Berková Z. Lacik J. Sedlacek O. Hoogenboom R. et al., A broad tuneable birdcage coil for mouse 1H/19F MR applications. J. Magn. Reson. 2021;329:107023. doi: 10.1016/j.jmr.2021.107023. doi: 10.1016/j.jmr.2021.107023. PubMed DOI

Švec P. Petrov O. V. Lang J. Štěpnička P. Groborz O. Dunlop D. et al., Fluorinated ferrocene moieties as a platform for redox-responsive polymer 19F MRI theranostics. Macromolecules. 2021;55:658–671. doi: 10.1021/acs.macromol.1c01723. doi: 10.1021/acs.macromol.1c01723. DOI

Sedlacek O. Jirak D. Galisova A. Jager E. Laaser J. E. Lodge T. P. et al., 19F magnetic resonance imaging of injectable polymeric implants with multiresponsive behavior. Chem. Mater. 2018;30:4892–4896. doi: 10.1021/acs.chemmater.8b02115. doi: 10.1021/acs.chemmater.8b02115. DOI

Güden-Silber T., Temme S., Jacoby C. and Flögel U., Biomedical 19F MRI using perfluorocarbons, in Preclinical MRI, Methods in Molecular Biology, ed. M. García Martín and P. López Larrubia, Humana Press, New York, 2018, vol. 1718, pp. 235–257, 10.1007/978-1-4939-7531-0_14 PubMed DOI

Babuka D. Kolouchova K. Hruby M. Groborz O. Tosner Z. Zhigunov A. et al., Investigation of the internal structure of thermoresponsive diblock poly(2-methyl-2-oxazoline)-b-poly[n-(2,2-difluoroethyl)acrylamide] copolymer nanoparticles. Eur. Polym. J. 2019;121:109306. doi: 10.1016/j.eurpolymj.2019.109306. doi: 10.1016/j.eurpolymj.2019.109306. DOI

Babuka D. Kolouchova K. Groborz O. Tosner Z. Zhigunov A. Stepanek P. et al., Internal structure of thermoresponsive physically crosslinked nanogel of poly[n-(2-hydroxypropyl)methacrylamide]-block-poly[n-(2,2-difluoroethyl)acrylamide], prominent 19F MRI Tracer. Nanomaterials. 2020;10:2231. doi: 10.3390/nano10112231. doi: 10.3390/nano10112231. PubMed DOI PMC

Kolouchova K. Groborz O. Cernochova Z. Skarkova A. Brabek J. Rosel D. et al., Thermo- and Ros-responsive self-assembled polymer nanoparticle tracers for 19F MRI theranostics. Biomacromolecules. 2021;22:2325–2337. doi: 10.1021/acs.biomac.0c01316. doi: 10.1021/acs.biomac.0c01316. PubMed DOI

Hruby M. Pouckova P. Zadinova M. Kucka J. Lebeda O. Thermoresponsive polymeric radionuclide delivery system—an injectable brachytherapy. Eur. J. Pharm. Sci. 2011;42:484–488. doi: 10.1016/j.ejps.2011.02.002. doi: 10.1016/j.ejps.2011.02.002. PubMed DOI

Ghuman H. Massensini A. R. Donnelly J. Kim S.-M. Medberry C. J. Badylak S. F. et al., ECM hydrogel for the treatment of stroke: characterization of the host cell infiltrate. Biomaterials. 2016;91:166–181. doi: 10.1016/j.biomaterials.2016.03.014. doi: 10.1016/j.biomaterials.2016.03.014. PubMed DOI PMC

Ghuman H. Gerwig M. Nicholls F. J. Liu J. R. Donnelly J. Badylak S. F. et al., Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume. Acta Biomater. 2017;63:50–63. doi: 10.1016/j.actbio.2017.09.011. doi: 10.1016/j.actbio.2017.09.011. PubMed DOI PMC

Kim M. J. I. Lee B. S. Chun C. J. Cho J.-K. Kim S.-Y. Song S.-C. Long-term theranostic hydrogel system for solid tumors. Biomaterials. 2012;33:2251–2259. doi: 10.1016/j.biomaterials.2011.11.083. doi: 10.1016/j.biomaterials.2011.11.083. PubMed DOI

Guarnieri M. Tyler B. M. DeTolla L. Zhao M. Kobrin B. Subcutaneous implants for long-acting drug therapy in laboratory animals may generate unintended drug reservoirs. J. Pharm. BioAllied Sci. 2014;6:38. doi: 10.4103/0975-7406.124315. doi: 10.4103/0975-7406.124315. PubMed DOI PMC

Bayat M. and Nasri S., Injectable microgel–hydrogel composites “Plum pudding gels”: new system for prolonged drug delivery, in Nanomaterials for Drug Delivery and Therapy, ed. A. M. Grumezescu, Elsevier, 2019, pp. 343–372, 10.1016/b978-0-12-816505-8.00001-1 DOI

Garello F. Terreno E. Sonosensitive MRI nanosystems as cancer theranostics: a recent update. Front. Chem. 2018;6:157. doi: 10.3389/fchem.2018.00157. doi: 10.3389/fchem.2018.00157. PubMed DOI PMC

Moreno Raja M., Lim P. Q., Wong Y. S., Xiong G. M., Zhang Y., Venkatraman S. and Huang Y., Polymeric nanomaterials, in Nanocarriers for Drug Delivery, ed. S. S. Mohapatra, S. Ranjan, N. Dasgupta, R. K. Mishra and S. Thomas, Elsevier, 2019, pp. 557–653, 10.1016/b978-0-12-814033-8.00018-7 DOI

Jeong Y. Hwang H. S. Na K. Theranostics and contrast agents for Magnetic Resonance Imaging. Biomater. Res. 2018;22:20. doi: 10.1186/s40824-018-0130-1. doi: 10.1186/s40824-018-0130-1. PubMed DOI PMC

Ma Z. Wan H. Wang W. Zhang X. Uno T. Yang Q. et al., A theranostic agent for cancer therapy and imaging in the second near-infrared window. Nano Res. 2018;12:273–279. doi: 10.1007/s12274-018-2210-x. doi: 10.1007/s12274-018-2210-x. PubMed DOI PMC

Jeelani S. Jagat Reddy R. C. Maheswaran T. Asokan G. S. Dany A. Anand B. Theranostics: a treasured tailor for tomorrow. J. Pharm. BioAllied Sci. 2014;6:6. doi: 10.4103/0975-7406.137249. doi: 10.4103/0975-7406.137249. PubMed DOI PMC

Kjær L. Thomsen C. Larsson H. B. Henriksen O. Ring P. Evaluation of biexponential relaxation processes by magnetic resonance imaging. Acta Radiol. 1988;29:473–480. doi: 10.3109/02841858809175023. doi: 10.1177/028418518802900418. PubMed DOI

Bogomolova A. Kaberov L. Sedlacek O. Filippov S. K. Stepanek P. Král V. et al., Double stimuli-responsive polymer systems: how to use crosstalk between pH- and thermosensitivity for drug depots. Eur. Polym. J. 2016;84:54–64. doi: 10.1016/j.eurpolymj.2016.09.010. doi: 10.1016/j.eurpolymj.2016.09.010. DOI

Piccinin M. A. and Schwartz J., Histology, Verhoeff Stain, StatPearls Publishing, Treasure Island, FL, 2020 PubMed

Vít M. Burian M. Gálisová A. Jirák D. Construction of a Wide tuneable Volume Coil for Small-Animal MR Imaging. Int. J. Eng. Sci. Invention. 2019;8:8–17.

Hall J. E., Hall M. E. and Guyton A. C., in Guyton and Hall Textbook of Medical Physiology, Elsevier, Philadelphia, PA, 2006, pp. 316–317

Gruber B. Froeling M. Leiner T. Klomp D. W. J. RF coils: a practical guide for nonphysicists. J. Magn. Reson. Imaging. 2018;48:590–604. doi: 10.1002/jmri.26187. doi: 10.1002/jmri.26187. PubMed DOI PMC

Rabyk M. Galisova A. Jiratova M. Patsula V. Srbova L. Loukotova L. et al., Mannan-based conjugates as a multimodal imaging platform for lymph nodes. J. Mater. Chem. B. 2018;6:2584–2596. doi: 10.1039/c7tb02888a. doi: 10.1039/C7TB02888A. PubMed DOI

Intramuscular Drug Administration, Neglected Factors in Pharmacology and Neuroscience Research – Biopharmaceutics, in Animal Characteristics Maintenance, Testing Conditions, ed. V. Claassen, 1994, pp. 23–34, 10.1016/b978-0-444-81871-3.50008-4 DOI

Kučka J. Hrubý M. Lebeda O. Biodistribution of a radiolabelled thermoresponsive polymer in mice. Appl. Radiat. Isot. 2010;68:1073–1078. doi: 10.1016/j.apradiso.2010.01.022. doi: 10.1016/j.apradiso.2010.01.022. PubMed DOI

Zhang Q. Weber C. Schubert U. S. Hoogenboom R. Thermoresponsive polymers with lower critical solution temperature: from fundamental aspects and measuring techniques to recommended turbidimetry conditions. Mater. Horiz. 2017;4:109–116. doi: 10.1039/c7mh00016b. doi: 10.1039/C7MH00016B. DOI

Schwartz L. Supuran C. Alfarouk K. The Warburg effect and the hallmarks of cancer. Anticancer Agents Med. Chem. 2017;17:164–170. doi: 10.2174/1871520616666161031143301. doi: 10.2174/1871520616666161031143301. PubMed DOI

Punnia-Moorthy A. Evaluation of pH changes in inflammation of the subcutaneous air pouch lining in the rat, induced by Carrageenan, dextran and Staphylococcus aureus. J. Oral Pathol. Med. 1987;16:36–44. doi: 10.1111/j.1600-0714.1987.tb00674.x. doi: 10.1111/j.1600-0714.1987.tb00674.x. PubMed DOI

Water-soluble fluorinated copolymers as highly sensitive 19F MRI tracers: From structure optimization to multimodal tumor imaging

Stimuli-Responsive Polymers for Advanced 19F Magnetic Resonance Imaging: From Chemical Design to Biomedical Applications