Enhanced Performance of Polymeric 19 F MRI Contrast Agents through Incorporation of Highly Water-Soluble Monomer MSEA Changkui Fu, †,‡ Cheng Zhang, †,‡ Hui Peng, †,‡ Felicity Han, † Carly Baker, † Yuao Wu, † Hang Ta, † and Andrew K. Whittaker* ,†,‡ † Australian Institute for Bioengineering and Nanotechnology and ‡ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD 4072, Australia * S Supporting Information ABSTRACT: 19 F magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique that shows tremen- dous potential for the diagnosis and monitoring of human diseases. Fluorinated compounds are commonly used as 19 F MRI contrast agents to develop “hot spot” imaging. To achieve high-resolution MR images, a high density of 19 F nuclei is required in the contrast agents. However, because of the inherent hydrophobicity of fluorinated moieties, aggrega- tion of 19 F contrast agents with high fluorine content is often observed in aqueous solution, resulting in attenuated MR signal and low sensitivity, thus significantly limiting their further biological applications. Here we report the synthesis and characterization of a series of polymeric 19 F MRI contrast agents with high fluorine content by copolymerizing the well- known fluorinated monomer 2,2,2-trifluoroethyl acrylate (TFEA) with a highly water-soluble monomer 2-(methylsulfinyl)ethyl acrylate (MSEA) using RAFT polymerization. We show that these polymeric contrast agents, although with high fluorine content, display remarkable imaging performance as evidenced by preferable relaxation properties and intense in vitro/in vivo MRI signals, demonstrating the huge potential for eventual clinical applications such as MRI-guided disease diagnosis and therapy. ■ INTRODUCTION Over the past few decades, magnetic resonance imaging (MRI) has been widely used in the clinic for disease diagnosis and monitoring of treatment due to advantages such as non- invasiveness, deep-tissue penetration, and excellent spatial resolution (submillimeter). 1 To better highlight the anatomical and pathological features of the tissue of interest, contrast agents are often required to improve the sensitivity of the MRI scan by enhancing the image contrast. 2 Paramagnetic or superparamagnetic metal-ion-based compounds such as gadolinium chelates and iron oxide nanoparticles have achieved large success as 1 H MRI contrast agents. 3-5 These agents can modulate the relaxation properties of nearby water molecules to induce additional contrast, allowing significantly improved visualization of the region of interest. Despite their success in the clinic, the metal-based contrast agents present several inherent disadvantages. Principally, the agents alter the relaxation properties of the surrounding water protons and hence are only detected indirectly. Hence, quantitative analysis is difficult. Also, the ubiquitous large content of water in tissues results in significant background signal interference, making it at times difficult to identify the target tissue. In addition, safety concerns are associated with the use of metal-based contrast agents. For example, gadolinium-based contrast agents have been reported to be involved in the development of nephrogenic systemic fibrosis in patients with impaired kidney function. 6,7 Gadolinium-based contrast agents can be retained in body including the brain for months or even years as warned by the US FDA recently. 8 The long-term retention of gadolinium is potentially a concern for both healthcare professionals and patients. A strategy to overcome the limitations of 1 H MRI is to develop probes based on nuclei other than the proton. 9-12 19 F MRI is a promising alternative to 1 H MRI due to the favorable NMR properties of 19 F such as large gyromagnetic ratio and high natural abundance. Fluorinated compounds are of course required as contrast agents for 19 F MRI. 13,14 In contrast to 1 H MRI contrast agents that affect the relaxation properties of nearby water molecules without being visualized directly, 19 F MRI contrast agents have an innate MR signal comparable to 1 H MRI to create “hot spot” images which are not obscured by the large pool of protons in the biological system. 15-18 Furthermore, thanks to the lack of endogenous MRI-detectable fluorine in the human body, a linear relationship between 19 F content and the MR intensity can be expected, allowing for quantitative applications in cell tracking for immunother- Received: June 5, 2018 Revised: July 16, 2018 Published: July 26, 2018 Article pubs.acs.org/Macromolecules Cite This: Macromolecules 2018, 51, 5875-5882 © 2018 American Chemical Society 5875 DOI: 10.1021/acs.macromol.8b01190 Macromolecules 2018, 51, 5875-5882 Downloaded via UNIV OF QUEENSLAND on August 16, 2018 at 23:27:10 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.