Mn(ii)-MOF nanoparticles conjugated with EOB-PEG as high-performance hepatobiliary-specific MRI contrast agents

Hepatobiliary magnetic resonance imaging (MRI) is a crucial diagnostic tool for early detection and staging of liver tumors. However, the currently available hepatobiliary-specific contrast agents (CAs), acyclic Gd chelates, suffer from limited kinetic stability and may pose serious toxicity risks to patients with specific functional impairments. In light of these concerns, Mn-based MRI CAs have gained increasing attention as potential alternatives to Gd-based agents, despite challenges in their stability and relaxivity. Herein, we present a novel hepatobiliary-specific CA in the form of Mn(II)-based metal-organic framework (MOF) nanoparticles conjugated with ethoxybenzyl-poly(ethylene glycol) (EOB-PEG) ligands. These nanoparticles exhibit significantly higher relaxivity (r₁ = 66.4 mM^-1 s^-1 in 4.5% HSA) compared to a commercial hepatobiliary-specific CA, Gd-EOB-DTPA (r₁ = 11.2 mM^-1 s^-1 in 4.5% HSA), along with excellent biocompatibility. This enables them to achieve equivalent imaging contrast with a substantially lower metal concentration (0.025 mmol Mn²⁺ per kg BW vs. 0.1 mmol Gd³⁺ per kg BW for the commercial Gd-EOB-DTPA). Furthermore, our MOF-based nanoparticles demonstrate precise diagnostic capabilities in vivo, as evidenced by their performance in orthotopic HCC mouse models. This progress holds great promise for the development of advanced hepatobiliary-specific CAs, which could significantly enhance early liver cancer diagnosis by providing clearer and safer imaging options.