Partially Fluorinated Copolymers as Oxygen Sensitive ¹⁹F MRI Agents

Abstract

Effective diagnosis of disease and itsp rogression can be aided by 19 Fm agnetic resonance imaging(MRI) techniques. Specifically,t he inherent sensitivity of the spin-lattice relaxationt ime (T 1)o f 19 Fn uclei to oxygen partial pressure makes 19 FMRI an attractive non-invasive approach to quantify tissue oxygenation in as patiotemporal manner. However,t here are only few materials with the adequate sensitivity to be used as oxygen-sensitive 19 FMRI agentsa t clinically relevant field strengths. Motivated by the limitations in current technologies, we reporth ighly fluorinated monomerst hat provide ap latform approach to realize water-soluble, partially fluorinated copolymers as 19 FMRI agents with the required sensitivityt oq uantify solution oxygenation at clinically relevant magnetic field strengths. The synthesis of as ystematic library of partially fluorinated co-polymers enabled ac omprehensive evaluationo fc opolymer structure-property relationships relevant to 19 FMRI. The highest-performing materialc ompositiond emonstrated a signal-to-noise ratio that corresponded to an apparent 19 F density of 220 mm,w hich surpasses the threshold of 126 mm 19 Fr equired for visualization on at hree Tesla clinical MRI. Furthermore, the T 1 of these high performing materials demonstrated al inear relationship with solution oxygenation, with oxygen sensitivity reaching 240 10 À5 mmHg À1 s À1. The relationships between material composition and 19 FMRI performance identified herein suggest general structureproperty criteria for the furtheri mprovement of modular, water-soluble 19 FMRI agents for quantifying oxygenation in environments relevant to medical imaging.

Machine Learning-Guided Discovery of 19F MRI Agents Enabled by Automated Copolymer Synthesis

“…The central dogma in this field is that copolymers with higher 19 F content have higher SNR in 19 F MRI experiments. 45,64,74,76,77 Considering the three partially fluorinated monomers chosen for this study (Figure 2A), and our previous observations 45 , we hypothesized that copolymers made with NonaFOEA would have the highest sensitivity given NonaFOEA has the highest weight percent (wt%) 19 F. The parallel coordinate diagram in Figure 5A collects data for copolymer composition, wt% 19 F, and SNR for each copolymer produced in this study. Initial evaluation of this data demonstrated an unexpected but clear discontinuity between wt% 19 F and SNR.…”

“…For example, Hedrick and coworkers developed a flow reactor capable of synthesizing 100 unique block copolymers in 8 minutes, but the technology relied on ring-opening polymerizations with reaction times of <1 second. 63 Unfortunately, the controlled radical polymerization techniques traditionally employed to make copolymer 19 F MRI agents suffer from reaction kinetics that are orders of magnitude slower than this example, 45,64 which required the design of a novel high-throughput flow reactor.…”

“…19 F MRI is a high contrast biomedical imaging modality with the potential to track cellular transport and quantitate oxygenation with spatiotemporal resolution. [41][42][43][44][45] Synthetic polymers represent attractive 19 F MRI agents due to their potential for multivalent displays of 19 F atoms and their synthetic modularity. Despite decades of effort reporting hundreds of copolymer 19 F MRI agents, challenges persist to develop 19 F MRI agents that are both water soluble and contain enough fluorine nuclei to be visualized on clinical 3 Tesla (T) MRI scanners.…”

Mapping the Morphological Landscape of Oligomeric Di-block Peptide Polymer Amphiphiles

“…Hansen solubility parameter (HSP) values [66,67] , calculated for each peptide using molecular dynamics (MD) simulations, suggest that the most hydrophilic peptide is XTEN1 followed by XTEN2, PAS1, and PAS2 (Figure S39a); however, while this calculation captures the effects of charge on hydrophilicity, it does not account for the effect of hydrogen bonding with water and thus underestimates the hydrophilicity of the PAS peptides [37] . By simulating hydrogen bonding of each peptide within a solvated environment using MD [69] , we found that the capacity for hydrogen bonding between the peptide and water varies significantly with sequence and length (Figure S39b). We experimentally corroborated these calculations by comparing HPLC retention time of the in a neutral solvent system that matched the pH of our assembly conditions (Figure S40).…”

Machine Learning-Guided Discovery of 19F MRI Agents Enabled by Automated Copolymer Synthesis

“…19 F MRI is a high contrast biomedical imaging modality with the potential to track cellular transport and quantitate oxygenation with spatiotemporal resolution. [41][42][43][44][45] Synthetic polymers represent attractive 19 F MRI agents due to their potential for multivalent displays of 19 F atoms and their synthetic modularity. Despite decades of effort reporting hundreds of copolymer 19 F MRI agents, challenges persist to develop 19 F MRI agents that are both water soluble and contain enough fluorine nuclei to be visualized on clinical 3 Tesla (T) MRI scanners.…”