Tumor microenvironment-responsive histidine modified-hyaluronic acid-based MnO₂ as in vivo MRI contrast agent

Tumor microenvironment (TME)-responsive manganese dioxide (MnO₂) nanoparticles as a good T₁ contrast agent could reduce unwanted toxicity and improve the accuracy of cancer detection. Despite these distinct advantages of MnO₂-based nanoparticles, their synthesis involves multi-step processes with relatively long synthesis times. In this study, we synthesized histidine-modified hyaluronic acid (HA-His), and the prepared HA-His conjugates quickly reduce permanganate to MnO₂, leading to facile production of HA-His/MnO₂ nanoparticles with good water-dispersibility and stability under biological conditions. The synthesized HA-His/MnO₂ nanoparticles readily responded to the TME (low pH, high H₂O₂, and high glutathione), and they were internalized into SCC7 cells with high CD44 expression. Moreover, the systemically administered HA-His/MnO₂ nanoparticles with biocompatibility were specifically accumulated in tumor tissues, thereby efficiently enhancing T₁ contrast in MRI. Therefore, the HA-His/MnO₂ nanoparticles synthesized herein can be used as a promising T₁ contrast agent for tumor MR imaging.