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 nanopreparation 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 a 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.