Ultrahigh magnetic resonance contrast switching with water gated polymer-silica nanoparticles Daohe Yuan 1 , Connor M. Ellis 1 , Ferenc E. Mózes 2 and Jason J. Davis 1 1 University of Oxford, Department of Chemistry, Oxford, United Kingdom 2 University of Oxford, Oxford Centre for Clinical Magnetic Resonance Research, Oxford, United Kingdom Introduction: Environmentally responsive gadolinium-based contrast agents (GBCAs) possess a powerful means to provide unique disease-specific insight by magnetic resonance imaging (MRI). 1 However, it remains a challenge to achieve large responses at clinically relevant fields. 2 In this work, 3 GBCA-based polymer-silica nanoparticles are generated with ultrahigh pH-dependent switches in MR contrast. The pH-responsive MR switches can be ascribed to the optimisation of outer-sphere relaxivities, which can be mediated by the capping effect of pore-internal water. Methods: Paramagnetic mesoporous silica nanoparticles (Gd-MSNs)
were initially synthesised by incorporating Gd-DOTA complexes into MSN nano-scaffolds. A pH-responsive poly(methacrylic acid) (pMAA) coating was subsequently grafted using a surface-initiated reversible addition- fragmentation chain transfer (SI-RAFT) polymerisation,
affording the final product which was denoted as pMAA-Gd-MSNs. The nanoparticles were fully characterised by a range of analytical techniques including dynamic light scattering, thermogravimetric analysis, inductively coupled plasma mass spectrometry, infrared spectroscopy, transmission electron microscopy, NMR, and clinical MR imaging. Results and Discussion:
The illustration of pMAA-Gd-MSNs is depicted in Figure 1a , possessing an immobilised water cap at the periphery of the Gd-MSN when pMAA is in its charged state and, therefore, exhibits a strong association with water. 4 Notably, there are dramatic enhancements in for pMAA-Gd-MSNs as the of pMAA is traversed ( Figure 1b , = 30.3 ± 3.2 mM –1 s –1 at 1.4 T, across 1.0 pH-unit, from pH 4.0 to pH 7.0). This “switch-on”
response is not observed in the absence of a pMAA polymer coating; native Gd-MSNs exhibit constant relaxivities across the full pH range. To highlight the clinical utility of the particles, spatially-resolved-mapping experiments on clinical imaging scanners were performed (1.5 T and 3 T; Figure 2a) . These switches in r1are the highest reported at both magnetic field strengths ( Figure 2b and Figure 2c , delta r1 switch= 50.5 mM –1 s –1 at 1.5 T and at r1 switch= 21.8 mM –1 s –1 at 3 T). Referring to a modified Freed equation, an entirely realistic 5 reduction in internal water diffusioncan account for the enhancements in r1(as shown in Figure 2d ). This is the first report highlighting the role of optimised outer-sphere relaxity, in designing a smart pH-responsive MR contrast agent. Conclusions: This work reports the synthesis and characterisation of paramagnetic inorganic-organic hybrid nanoparticles that exhibit a pH-mediated contrast switch that is sharp, of an unprecedented magnitude, clinically relevant, and mechanistically new. References 1. J. Wahsner, E. M. Gale, A. Rodríguez-Rodríguez and P. Caravan, Chem Rev , 2019, 119 , 957-1057.G.-L. Davies, I. Kramberger and J. J. Davis, Chem. Commun. , 2013, 49 , 9704-9721. 2. D. Yuan, C. M. Ellis, F. Mozes and J. J. Davis, Chem. Commun. , 2023, Accepted Manuscript. doi.org/10.1039/ D3CC01205KS.-P. Ju, W.-J. Lee, C.-I. Huang, W.-Z. Cheng and Y.-T. Chung, J. Chem. Phys. , 2007, 126 , 224901.M. Weigler, E. Winter, B. Kresse, M. Brodrecht, G. Buntkowsky and M. Vogel, Phys. Chem. Chem. Phys. , 2020, 22 , 13989-13998.
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