Facile Construction of Manganese-based Contrast Agent with High T1 Relaxivity for Magnetic Resonance Imaging via Flash Technology-based Self-assembly

To address the limitations of low relaxivity and physiological toxicity in commercial gadolinium-based contrast agents for magnetic resonance imaging (MRI), a novel manganese chelate macromolecular system was developed using a flash nano-preparation technique. Herein, the approach applying an instantaneous fluid device incorporated gallic acid, dopamine and Mn2+ to perform in-situ polymerization of dopamine and covalent binding with albumin in a nanoconfined environment. This controllable self-assembly process characterized by its scalability and reproducibility was suitable for industrial-scale production. Under optimized flow rates and material ratios, the synthesized ultrasmall protein-based system, Mn-GA@BSA@DA, exhibited excellent aqueous dispersion with an average size of approximately 18 nm, allowing for long-term lyophilized powder storage. More importantly, the nanosystem demonstrated superior MRI-T  1 relaxivity, significantly surpassing that of clinical Gadopentetate dimeglumine, with a high value around 18.5 mM−1 s−1 and a low r  2/r  1 ratio (< 5 at 3.0 T). Furthermore, this Mn-GA@BSA@DA contrast agent was endowed with tumor-targeting effects and long MRI monitoring window period for the liver, gallbladder and renal tubules. The metal chelation within the nanoagent minimizes Mn2+ release; importantly, the antioxidant components, gallic acid and dopamine, significantly inhibit the Fenton reaction-induced toxicity, enhancing biocompatibility. Therefore, this study presents a simple and scalable production technique for a kind of MRI-T  1 weighted contrast agent with high relaxivity and biocompatibility, offering a promising alternative to commercial Gd chelates.