Over the last few years, the development and relevance of 19F magnetic resonance imaging (MRI) for use in clinical practice has emerged. MRI using fluorinated probes enables the achievement of a specific signal with high contrast in MRI images. However, to ensure sufficient sensitivity of 19F MRI, fluorine probes with a high content of chemically equivalent fluorine atoms are required. The majority of 19F MRI agents are perfluorocarbon emulsions, which have a broad range of applications in molecular imaging, although the content of fluorine atoms in these molecules is limited. In this review, we focus mainly on polymer probes that allow higher fluorine content and represent versatile platforms with properties tailorable to a plethora of biomedical in vivo applications. We discuss the chemical development, up to the first imaging applications, of these promising fluorine probes, including injectable polymers that form depots that are intended for possible use in cancer therapy.

Faculty of Health Studies Technical University of Liberec Studentská 1402 2 461 17 Liberec 1 Czech Republic

Institute for Clinical and Experimental Medicine Vídeňská 9 140 21 Prague 4 Czech Republic

Institute of Biophysics and Informatics 1st Medicine Faculty Charles University Salmovská 1 120 00 Prague Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského sq 2 162 06 Prague 6 Czech Republic

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Ruiz-Cabello J, Barnett BP, Bottomley PA, Bulte JWM. Fluorine (F-19) MRS and MRI in biomedicine. NMR Biomed. 2011;24(2):114–129. PubMed PMC

Peterson KL, Srivastava K, Pierre VC (2018) Fluorinated paramagnetic complexes: sensitive and responsive probes for magnetic resonance spectroscopy and imaging. Front Chem 6 PubMed PMC

Yu JX, Hallac RR, Chiguru S, Mason RP. New frontiers and developing applications in F-19 NMR. Prog Nucl Mag Res Sp. 2013;70:25–49. PubMed PMC

Srinivas M, Heerschap A, Ahrens ET, Figdor CG, de Vries IJM. F-19 MRI for quantitative in vivo cell tracking. Trends Biotechnol. 2010;28(7):363–370. PubMed PMC

Bulte JW. Hot spot MRI emerges from the background. Nat Biotechnol. 2005;23(8):945–946. PubMed

Blahut J, Bernasek K, Galisova A, Herynek V, Cisarova I, Kotek J, Lang J, Matejkova S, Hermann P. Paramagnetic (19)F relaxation enhancement in Nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for (19)F MRI. Inorg Chem. 2017;56(21):13337–13348. PubMed

Knight JC, Edwards PG, Paisey SJ. Fluorinated contrast agents for magnetic resonance imaging; a review of recent developments. Rsc Adv. 2011;1(8):1415–1425.

Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol. 2005;23(8):983–987. PubMed

Fink C, Gaudet JM, Fox MS, Bhatt S, Viswanathan S, Smith M, Chin J, Foster PJ, Dekaban GA. (19)F-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. PubMed PMC

Gaudet JM, Ribot EJ, Chen Y, Gilbert KM, Foster PJ. Tracking the fate of stem cell implants with fluorine-19 MRI. PLoS One. 2015;10(3):e0118544. PubMed PMC

Srinivas M, Morel PA, Ernst LA, Laidlaw DH, Ahrens ET. Fluorine-19 MRI for visualization and quantification of cell migration in a diabetes model. Magn Reson Med. 2007;58(4):725–734. PubMed

Ahrens ET, Helfer BM, O’Hanlon CF, Schirda C. Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19 MRI. Magn Reson Med. 2014;72(6):1696–1701. PubMed PMC

Boehm-Sturm P, Aswendt M, Minassian A, Michalk S, Mengler L, Adamczak J, Mezzanotte L, Lowik C, Hoehn M. A multi-modality platform to image stem cell graft survival in the naive and stroke-damaged mouse brain. Biomaterials. 2014;35(7):2218–2226. PubMed

Tennstaedt A, Mastropietro A, Nelles M, Beyrau A, Hoehn M. In vivo fate imaging of intracerebral stem cell grafts in mouse brain. PLoS One. 2015;10(12):e0144262. PubMed PMC

Constantinides C, Maguire M, McNeill E, Carnicer R, Swider E, Srinivas M, Carr CA, Schneider JE. Fast, quantitative, murine cardiac 19F MRI/MRS of PFCE-labeled progenitor stem cells and macrophages. PLoS One. 2018;13(1):e0190558. PubMed PMC

Temme S, Bonner F, Schrader J, Flogel U. 19F magnetic resonance imaging of endogenous macrophages in inflammation. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4(3):329–343. PubMed

Liang S, Louchami K, Holvoet B, Verbeke R, Deroose CM, Manshian B, Soenen SJ, Lentacker I, Himmelreich U. Tri-modal in vivo imaging of pancreatic islets transplanted subcutaneously in mice. Mol Imaging Biol. 2018 PubMed

Barnett BP, Ruiz-Cabello J, Hota P, Ouwerkerk R, Shamblott MJ, Lauzon C, Walczak P, Gilson WD, Chacko VP, Kraitchman DL, Arepally A, Bulte JW. Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets. Contrast Media Mol Imaging. 2011;6(4):251–259. PubMed PMC

Rolfe BE, Blakey I, Squires O, Peng H, Boase NRB, Alexander C, Parsons PG, Boyle GM, Whittaker AK, Thurecht KJ. Multimodal polymer nanoparticles with combined F-19 magnetic resonance and optical detection for tunable, targeted, multimodal imaging in vivo. J Am Chem Soc. 2014;136(6):2413–2419. PubMed

Oishi M, Sumitani S, Nagasaki Y. On-off regulation of F-19 magnetic resonance signals based on pH-sensitive PEGylated nanogels for potential tumor-specific smart F-19 MRI probes. Bioconjugate Chem. 2007;18(5):1379–1382. PubMed

Young SW, Enzmann DR, Long DM, Muller HH. Perfluoroctylbromide contrast enhancement of malignant neoplasms: preliminary observations. AJR Am J Roentgenol. 1981;137(1):141–146. PubMed

Zhang C, Moonshi SS, Wang W, Ta HT, Han Y, Han FY, Peng H, Kral P, Rolfe BE, Gooding JJ, Gaus K, Whittaker AK. High F-content perfluoropolyether-based nanoparticles for targeted detection of breast cancer by (19)F magnetic resonance and optical imaging. ACS Nano. 2018;12(9):9162–9176. PubMed

Flogel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, Schubert R, Schrader J. In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation. 2008;118(2):140–148. PubMed PMC

Ahrens ET, Young WB, Xu H, Pusateri LK. Rapid quantification of inflammation in tissue samples using perfluorocarbon emulsion and fluorine-19 nuclear magnetic resonance. Biotechniques. 2011;50(4):229–234. PubMed PMC

Murugesan R, English S, Reijnders K, Yamada K, Cook JA, Mitchell JB, Subramanian S, Krishna MC. Fluorine electron double resonance imaging for 19F MRI in low magnetic fields. Magn Reson Med. 2002;48(3):523–529. PubMed

Waiczies H, Lepore S, Drechsler S, Qadri F, Purfurst B, Sydow K, Dathe M, Kuhne A, Lindel T, Hoffmann W, Pohlmann A, Niendorf T, Waiczies S. Visualizing brain inflammation with a shingled-leg radio-frequency head probe for 19F/1H MRI. Sci Rep. 2013;3:1280. PubMed PMC

Fox MS, Gaudet JM, Foster PJ. Fluorine-19 MRI contrast agents for cell tracking and lung imaging. Magn Reson Insights. 2015;8(Suppl 1):53–67. PubMed PMC

Morawski AM, Winter PM, Yu X, Fuhrhop RW, Scott MJ, Hockett F, Robertson JD, Gaffney PJ, Lanza GM, Wickline SA. Quantitative “magnetic resonance immunohistochemistry” with ligand-targeted (19)F nanoparticles. Magn Reson Med. 2004;52(6):1255–1262. PubMed

Higuchi M, Iwata N, Matsuba Y, Sato K, Sasamoto K, Saido TC. 19F and 1H MRI detection of amyloid beta plaques in vivo. Nat Neurosci. 2005;8(4):527–533. PubMed

Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy EK, Robertson JD, Lanza GM, Wickline SA. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation. 2003;108(18):2270–2274. PubMed

Thomas SR, Pratt RG, Millard RW, Samaratunga RC, Shiferaw Y, McGoron AJ, Tan KK. In vivo PO2 imaging in the porcine model with perfluorocarbon F-19 NMR at low field. Magn Reson Imaging. 1996;14(1):103–114. PubMed

Stevens AN, Morris PG, Iles RA, Sheldon PW, Griffiths JR. 5-fluorouracil metabolism monitored invivo by F-19 Nmr. Brit J Cancer. 1984;50(1):113–117. PubMed PMC

Deutsch CJ, Taylor JS. New class of 19F pH indicators: fluoroanilines. Biophys J. 1989;55(4):799–804. PubMed PMC

Deutsch CJ, Taylor JS. Intracellular pH as measured by 19F NMR. Ann N Y Acad Sci. 1987;508:33–47. PubMed

Metcalfe JC, Hesketh TR, Smith GA. Free cytosolic Ca-2 + measurements with fluorine labeled indicators using F-19-Nmr. Cell Calcium. 1985;6(1–2):183–195. PubMed

Du WJ, Xu ZQ, Nystrom AM, Zhang K, Leonard JR, Wooley KL. F-19- and fluorescently labeled micelles as nanoscopic assemblies for chemotherapeutic Delivery. Bioconjugate Chem. 2008;19(12):2492–2498. PubMed PMC

Schmieder AH, Caruthers SD, Keupp J, Wickline SA, Lanza GM. Recent advances in (19)Fluorine magnetic resonance imaging with perfluorocarbon emulsions. Engineering (Beijing) 2015;1(4):475–489. PubMed PMC

Ashur I, Allouche-Arnon H, Bar-Shir A. Calcium fluoride nanocrystals: tracers for in vivo (19) F magnetic resonance imaging. Angew Chem Int Ed Engl. 2018;57(25):7478–7482. PubMed

Kolouchova K, Sedlacek O, Jirak D, Babuka D, Blahut J, Kotek J, Vit M, Trousil J, Konefal R, Janouskova O, Podhorska B, Slouf M, Hruby M. Self-assembled thermoresponsive polymeric nanogels for (19)F MR imaging. Biomacromolecules. 2018 PubMed

Sedlacek O, Jirák D, Gálisová A, Jager E, Laaser JE, Lodge TP, Stepanek P, Hrubý M. 19F magnetic resonance imaging of injectable polymeric implants with multiresponsive behavior. Chem Mater. 2018;30(15):4892–4896.

Peng H, Blakey I, Dargaville B, Rasoul F, Whittaker AK. Effect of solvent quality on the solution properties of assemblies of amphiphilic diblock copolymers as potential F-19 MRI agents. Abstr Pap Am Chem. 2009;S:238.

Tirotta I, Mastropietro A, Cordiglieri C, Gazzera L, Baggi F, Baselli G, Bruzzone MG, Zucca I, Cavallo G, Terraneo G, Baldelli Bombelli F, Metrangolo P, Resnati G. A superfluorinated molecular probe for highly sensitive in vivo(19)F-MRI. J Am Chem Soc. 2014;136(24):8524–8527. PubMed

Gálisova A, Herynek V, Swider E, Sticová E, Pátiková A, Kosinová L, Kříž J, Hájek M, Srinivas M, Jirák D. A trimodal imaging platform for tracking viable transplanted pancreatic islets in vivo: 19F MR, fluorescence and bioluminescence imaging. Mol Imaging Biol. 2018 PubMed PMC

Srinivas M, Boehm-Sturm P, Figdor CG, de Vries IJ, Hoehn M. Labeling cells for in vivo tracking using (19)F MRI. Biomaterials. 2012;33(34):8830–8840. PubMed

Liang S, Dresselaers T, Louchami K, Zhu C, Liu Y, Himmelreich U. Comparison of different compressed sensing algorithms for low SNR (19) F MRI applications-Imaging of transplanted pancreatic islets and cells labeled with perfluorocarbons. NMR Biomed. 2017 PubMed

Waiczies H, Guenther M, Skodowski J, Lepore S, Pohlmann A, Niendorf T, Waiczies S. Monitoring dendritic cell migration using 19F/1H magnetic resonance imaging. J Vis Exp. 2013;73:e50251. PubMed PMC

Weibel S, Basse-Luesebrink TC, Hess M, Hofmann E, Seubert C, Langbein-Laugwitz J, Gentschev I, Sturm VJF, Ye Y, Kampf T, Jakob PM, Szalay AA. Imaging of intratumoral inflammation during oncolytic virotherapy of tumors by F-19-magnetic resonance imaging (MRI) Plos One. 2013;8(2):e56317. PubMed PMC

Ahrens ET, Bulte JWM. Tracking immune cells in vivo using magnetic resonance imaging. Nat Rev Immunol. 2013;13(10):755–763. PubMed PMC

Stoll G, Basse-Lusebrink T, Weise G, Jakob P. Visualization of inflammation using (19) F-magnetic resonance imaging and perfluorocarbons. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4(4):438–447. PubMed

Nakstad B, Kahler H, Wolfson MR, Lindemann R, Fugelseth D, Shaffer TH, Lyberg T. Perfluorocarbon chemicals do not induce inflammatory responses in human blood leukocytes. Pediatr Res. 1999;45(4):214a.

Nystrom AM, Bartels JW, Du W, Wooley KL. Perfluorocarbon-loaded shell crosslinked knedel-like nanoparticles: lessons regarding polymer mobility and self-assembly. J Polym Sci Pol Chem. 2009;47(4):1023–1037. PubMed PMC

Cheng C, Powell KT, Khoshdel E, Wooley KL. Polydimethylsiloxane-(PDMS-) grafted fluorocopolymers by a “grafting through” strategy based on atom transfer radical (Co)polymerization. Macromolecules. 2007;40(20):7195–7207.

Ahrens ET, Zhong J. In vivo MRI cell tracking using perfluorocarbon probes and fluorine-19 detection. NMR Biomed. 2013;26(7):860–871. PubMed PMC

Smith GA, Hesketh RT, Metcalfe JC, Feeney J, Morris PG. Intracellular calcium measurements by F-19 Nmr of fluorine-labeled chelators. Proc Natl Acad Sci-Biol. 1983;80(23):7178–7182. PubMed PMC

Robinson SP, Griffiths JR. Current issues in the utility of F-19 nuclear magnetic resonance methodologies for the assessment of tumour hypoxia. Philos T Roy Soc B. 2004;359(1446):987–996. PubMed PMC

Bar-Shir A, Yadav NN, Gilad AA, van Zijl PCM, McMahon MT, Bulte JWM. Single F-19 probe for simultaneous detection of multiple metal ions using miCEST MRI. J Am Chem Soc. 2015;137(1):78–81. PubMed PMC

Srinivas M, Cruz LJ, Bonetto F, Heerschap A, Figdor CG, de Vries IJ. Customizable, multi-functional fluorocarbon nanoparticles for quantitative in vivo imaging using 19F MRI and optical imaging. Biomaterials. 2010;31(27):7070–7077. PubMed

Jacoby C, Temme S, Mayenfels F, Benoit N, Krafft MP, Schubert R, Schrader J, Flogel U. Probing different perfluorocarbons for in vivo inflammation imaging by 19F MRI: image reconstruction, biological half-lives and sensitivity. NMR Biomed. 2014;27(3):261–271. PubMed

Krafft MP, Riess JG. Perfluorocarbons: Life sciences and biomedical uses—dedicated to the memory of Professor Guy Ourisson, a true RENAISSANCE man. J Polym Sci Pol Chem. 2007;45(7):1185–1198.

Mason RP, Antich PP, Babcock EE, Gerberich JL, Nunnally RL. Perfluorocarbon imaging invivo—a F-19 Mri study in tumor-bearing mice. Magn Reson Imaging. 1989;7(5):475–485. PubMed

Shimizu M, Kobayashi T, Morimoto H, Matsuura N, Shimano T, Nomura N, Itoh S, Yamazaki M, Iriguchi N, Yamamoto T, Yamai S, Furuta T, Maki T, Mori T. Tumor imaging with anti-Cea antibody labeled F-19 emulsion. Magnet Reson Med. 1987;5(3):290–295. PubMed

Zhang C, Moonshi SS, Han YX, Puttick S, Peng H, Magoling BJA, Reid LC, Bernardi S, Searles DJ, Kral P, Whittaker AK. PFPE-based polymeric F-19 MRI agents: a new class of contrast agents with outstanding sensitivity. Macromolecules. 2017;50(15):5953–5963.

Peng H, Thurecht KJ, Blakey I, Taran E, Whittaker AK. Effect of solvent quality on the solution properties of assemblies of partially fluorinated amphiphilic diblock copolymers. Macromolecules. 2012;45(21):8681–8690.

Peng H, Blakey I, Dargaville B, Rasoul F, Rose S, Whittaker AK. Synthesis and evaluation of partly fluorinated block copolymers as MRI imaging agents. Biomacromol. 2009;10(2):374–381. PubMed

Mao J, Ni PH, Mai YY, Yan DY. Multicompartment micelles from hyperbranched star-block copolymers containing polycations and fluoropolymer segment. Langmuir. 2007;23(9):5127–5134. PubMed

Yusa S, Yamamoto T, Hashidzume A, Morishima Y. Synthesis and characterization of self-associative perfluoroalkyl-end-capped polystyrene. Polym J. 2002;34(3):117–124.

Andruzzi L, Chiellini E, Galli G, Li XF, Kang SH, Ober CK. Engineering low surface energy polymers through molecular design: synthetic routes to fluorinated polystyrene-based block copolymers. J Mater Chem. 2002;12(6):1684–1692.

Shi ZQ, Holdcroft S. Synthesis and proton conductivity of partially sulfonated poly([vinylidene difluoride-co-hexafluoropropylene]-b-styrene) block copolymers. Macromolecules. 2005;38(10):4193–4201.

Destarac M, Matyjaszewski K, Silverman E, Ameduri B, Boutevin B. Atom transfer radical polymerization initiated with vinylidene fluoride telomers. Macromolecules. 2000;33(13):4613–4615.

Lebreton P, Ameduri B, Boutevin B, Corpart JM. Use of original omega-perfluorinated dithioesters for the synthesis of well-controlled polymers by reversible addition-fragmentation chain transfer (RAFT) Macromol Chem Phys. 2002;203(3):522–537.

Monteiro MJ, Adamy MM, Leeuwen BJ, van Herk AM, Destarac M. A “living” radical ab initio emulsion polymerization of styrene using a fluorinated xanthate agent. Macromolecules. 2005;38(5):1538–1541.

Sawada H. Fluorinated peroxides. Chem Rev. 1996;96(5):1779–1808. PubMed

Sawada H, Ikeno K, Kawase T. Synthesis of amphiphilic fluoroalkoxyl end-capped cooligomers containing oxime-blocked isocyanato segments: architecture and applications of new self-assembled fluorinated molecular aggregates. Macromolecules. 2002;35(11):4306–4313.

Boutevin B, Diaf KO, Pietrasanta Y, Taha M. Synthesis of Block cotelomers involving a perfluorinated chain and a hydrophilic chain. 1. Use of Fluorinated Telogens with Trichloromethyl End Groups. J Polym Sci Pol Chem. 1986;24(11):3129–3137.

Su ZH, Wu DC, Hsu SL, McCarthy TJ. Adsorption of end-functionalized poly(ethylene oxide)s to the poly(ethylene oxide)-air interface. Macromolecules. 1997;30(4):840–845.

Kaberov LI, Verbraeken B, Hruby M, Riabtseva A, Kovacik L, Kereiche S, Brus J, Stepanek P, Hoogenboom R, Filippov SK. Novel triphilic block copolymers based on poly(2-methyl-2oxazoline)-block-poly(2-octyl-2-oxazoline) with different terminal perfluoroalkyl fragments: synthesis and self-assembly behaviour. Eur Polym J. 2017;88:645–655.

Aasen SN, Pospisilova A, Eichler TW, Panek J, Hruby M, Stepanek P, Spriet E, Jirak D, Skaftnesmo KO, Thorsen F. A novel nanoprobe for multimodal imaging is effectively incorporated into human melanoma metastatic cell lines. Int J Mol Sci. 2015;16(9):21658–21680. PubMed PMC

Langereis S, Keupp J, van Velthoven JLJ, de Roos IHC, Burdinski D, Pikkemaat JA, Grull H. A temperature-sensitive liposomal H-1 CEST and F-19 contrast agent for mr image-guided drug delivery. J Am Chem Soc. 2009;131(4):1380–1381. PubMed

Navath RS, Menjoge AR, Wang B, Romero R, Kannan S, Kannan RM. Amino acid-functionalized dendrimers with heterobifunctional chemoselective peripheral groups for drug delivery applications. Biomacromol. 2010;11(6):1544–1563. PubMed PMC

Thurecht KJ, Blakey I, Peng H, Squires O, Hsu S, Alexander C, Whittaker AK. Functional hyperbranched polymers: toward targeted in vivo F-19 magnetic resonance imaging using designed macromolecules. J Am Chem Soc. 2010;132(15):5336–5337. PubMed

Rabyk M, Galisova A, Jiratova M, Patsula V, Srbova L, Loukotova L, Parnica J, Jirak D, Stepanek P, Hruby M. Mannan-based conjugates as a multimodal imaging platform for lymph nodes. J Mater Chem B. 2018;6(17):2584–2596. PubMed

Hruby M, Filippov SK, Stepanek P. Supramolecular structures and self-association processes in polymer systems. Physiol Res 65 (Supplementum. 2016;2):S165–S178. PubMed

Skodova M, Hruby M, Filippov SK, Karlsson G, Mackova H, Spirkova M, Kankova D, Steinhart M, Stepanek P, Ulbrich K. Novel polymeric nanoparticles assembled by metal ion addition. Macromol Chem Phys. 2011;212(21):2339–2348.

Hruby M, Konak C, Kucka J, Vetrik M, Filippov SK, Vetvicka D, Mackova H, Karlsson G, Edwards K, Rihova B, Ulbrich K. Thermoresponsive, hydrolytically degradable polymer micelles intended for radionuclide delivery. Macromol Biosci. 2009;9(10):1016–1027. PubMed

Dardzinski BJ, Sotak CH. Rapid tissue oxygen tension mapping using 19F inversion-recovery echo-planar imaging of perfluoro-15-crown-5-ether. Magn Reson Med. 1994;32(1):88–97. PubMed

Lee H, Price RR, Holburn GE, Partain CL, Adams MD, Cacheris WP. In vivo fluorine-19 MR imaging: relaxation enhancement with Gd-DTPA. J Magn Reson Imaging. 1994;4(4):609–613. PubMed

Nam SY, Ricles LM, Suggs LJ, Emelianov SY. Imaging strategies for tissue engineering applications. Tissue Eng Part B-Re. 2015;21(1):88–102. PubMed PMC

Chalmers KH, Kenwright AM, Parker D, Blamire AM. (19)F-lanthanide complexes with increased sensitivity for (19)F-MRI: optimization of the MR acquisition. Magnet Reson Med. 2011;66(4):931–936. PubMed

Bouchoucha M, van Heeswijk RB, Gossuin Y, Kleitz F, Fortin MA. Fluorinated mesoporous silica nanoparticles for binuclear probes in H-1 and F-19 magnetic resonance imaging. Langmuir. 2017;33(40):10531–10542. PubMed

Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond) 2008;3(5):703–717. PubMed PMC

Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond) 2011;6(4):715–728. PubMed PMC

Brown GO, Bergquist C, Ferm P, Wooley KL. Unusual, promoted release of guests from amphiphilic cross-linked polymer networks. J Am Chem Soc. 2005;127(32):11238–11239. PubMed

Du WJ, Nystrom AM, Zhang L, Powell KT, Li YL, Cheng C, Wickline SA, Wooley KL. Amphiphilic hyperbranched fluoropolymers as nanoscopic (19)F magnetic resonance imaging agent assemblies. Biomacromol. 2008;9(10):2826–2833. PubMed PMC

Nurmi L, Peng H, Seppala J, Haddleton DM, Blakey I, Whittaker AK. Synthesis and evaluation of partly fluorinated polyelectrolytes as components in F-19 MRI-detectable nanoparticles. Polym Chem-Uk. 2010;1(7):1039–1047.

Loukotova L, Kucka J, Rabyk M, Hocherl A, Venclikova K, Janouskova O, Paral P, Kolarova V, Heizer T, Sefc L, Stepanek P, Hruby M. Thermoresponsive beta-glucan-based polymers for bimodal immunoradiotherapy—are they able to promote the immune system? J Control Release. 2017;268:78–91. PubMed

Zhang H, Ni PH, He JL, Liu CC. Novel fluoroalkyl end-capped amphiphilic diblock copolymers with pH/temperature response and self-assembly behavior. Langmuir. 2008;24(9):4647–4654. PubMed

Hoffman AS. The origins and evolution of “controlled” drug delivery systems. J Control Release. 2008;132(3):153–163. PubMed

Maeda H. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug Chem. 2010;21(5):797–802. PubMed

Talelli M, Rijcken CJ, van Nostrum CF, Storm G, Hennink WE. Micelles based on HPMA copolymers. Adv Drug Deliv Rev. 2010;62(2):231–239. PubMed

Hruby M, Filippov SK, Panek J, Novakova M, Mackova H, Kucka J, Vetvicka D, Ulbrich K. Polyoxazoline thermoresponsive micelles as radionuclide delivery systems. Macromol Biosci. 2010;10(8):916–924. PubMed

Jiratova M, Pospisilova A, Rabyk M, Parizek M, Kovar J, Galisova A, Hruby M, Jirak D. Biological characterization of a novel hybrid copolymer carrier system based on glycogen. Drug Deliv Transl Res. 2018;8(1):73–82. PubMed

Kucka J, Hruby M, Konak C, Kozempel J, Lebeda O. Astatination of nanoparticles containing silver as possible carriers of 211At. Appl Radiat Isot. 2006;64(2):201–206. PubMed

Sedlacek O, Monnery BD, Filippov SK, Hoogenboom R, Hruby M. Poly(2-oxazoline)s–are they more advantageous for biomedical applications than other polymers? Macromol Rapid Commun. 2012;33(19):1648–1662. PubMed

Fu CK, Herbst S, Zhang C, Whittaker AK. Polymeric F-19 MRI agents responsive to reactive oxygen species. Polym Chem-Uk. 2017;8(31):4585–4595.

Bogomolova A, Kaberov L, Sedlacek O, Filippov SK, Stepanek P, Kral V, Wang XY, Liu SL, Ye XD, Hruby M. Double stimuli-responsive polymer systems: how to use crosstalk between pH- and thermosensitivity for drug depots. Eur Polym J. 2016;84:54–64.

Schmaljohann D. Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliver Rev. 2006;58(15):1655–1670. PubMed

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