Lanthanide-Based Hybrid Polyion Complexes for use as ParaCEST MRI Contrast Agents

Cabell B. Eades, Diba Allameh Zadeh, Jared I. Bowman, Daniel R. Talham*, Brent S. Sumerlin*

University of Florida

Development of more efficacious and safe MRI contrast agents is paramount to improving the imaging and diagnosis of disease. To that extent,  we are developing macromolecular contrast agents that exhibit Paramagnetic Chemical Exchange Saturation Transfer (ParaCEST) capabilities to provide contrast in MRI images. Unlike conventional MRI contrast agents, which provide contrast by shortening the spin-lattice (T₁) relaxation of protons in the tissue of interest, ParaCEST agents function by magnetization transfer. This occurs when exchangeable protons associated with the ParaCEST agent are saturated with a specific radiofrequency pulse and exchange with bulk water protons in the tissue of interest. This results in a decrease of the local water signal with respect to the bulk water signal, leading to contrast. In our macromolecular ParaCEST agents, the exchange rate of water molecules in and out of the core is crucial to their efficacy as contrast agents. Herein, we have synthesized multiple different double-hydrophilic block copolymers (DHBCs), self-assembled them into hybrid polyion complexes (HPICs) with chemically distinct coronae, and are currently gauging the efficacy as ParaCEST agents of each. HPIC fabrication is accomplished by the addition of metal salts to aqueous solutions of tailor-made DHBCs. These DHBCs feature neutrally charged coronal, or stabilizing blocks, followed by core-forming polyanion blocks. Upon the addition of water-soluble metal salts, primarily CaCl₂ and Eu(NO₃)₃, DyCl₃, or TmCl₃, the core-forming polyanion blocks electrostatically complex with the metal cations, inducing the self-assembly of the DHBCs into the final spherical HPICs. These range in size from 25-70 nm depending on the exact DHBC/metal ion formulation.