Hypoxia-Responsive T-2-to-T-1 Dynamically Switchable Extremely Small Iron Oxide Nanoparticles for Sensitive Tumor Imaging In Vivo

To realize the accurate diagnosis of tumors by magneticresonanceimaging (MRI), switchable magnetic resonance contrast agents (CAs)between T-1 and T-2 contrast enhancement thatare constructed based on extremely small iron oxide nanoparticles(ESIONPs) have been developed in recent years. We herein report, forthe first time, a novel ESIONP-based nanocluster (named EAmP), whichexhibited hypoxia responsiveness to the tumor microenvironment andoffered a T-2-to-T-1-switchable contrast enhancementfunction, effectively distinguishing between the normal tissue andtumor tissue. In detail, active perfluorophenyl ester-modified ESIONPswith a diameter of approximately 3.6 nm were initially synthesized,and then 4,4 & PRIME;-azodianiline was used as a cross-linker to facilitatethe formation of nanoclusters from ESIONPs through the reaction betweenthe active ester and amine. Finally, poly(ethylene glycol) was furthermodified onto nanoclusters by utilizing the remaining active esterresidues. The resulting EAmP demonstrated satisfactory colloidal stabilityand favorable biosafety and exhibited a desired T-2-to-T-1-switchable function, as evidenced by conversion from nanoclusterto the dispersed state and a significant decrease in the r (2)/r (1) ratio from 14.86 to 1.61when exposed to a mimical hypoxic environment in the solution. Moreover,EAmP could decompose into dispersed ESIONPs at the tumor region, resultingin a switch from T-2 to T-1 contrast enhancement.This T-2-to-T-1-switchable contrast agent offershigh sensitivity and signal-to-noise ratio to realize the accuratediagnosis of tumors. In conclusion, hypoxia-responsive EAmP is a potentialMRI nanoprobe for improving the diagnostic accuracy of solid tumors.

Automated summary

To achieve accurate diagnosis of tumors using MRI, switchable magnetic resonance contrast agents (CAs) that can enhance T-1 and T-2 contrast have been developed based on extremely small iron oxide nanoparticles (ESIONPs). In this study, a hypoxia-responsive ESIONP-based nanocluster, named EAmP, was developed for the first time. EAmP exhibited a T-2-to-T-1 switchable contrast enhancement function, effectively differentiating between normal tissue and tumor tissue. This switchable contrast agent offers high sensitivity and signal-to-noise ratio for the accurate diagnosis of tumors, making it a potential MRI nanoprobe for improving diagnostic accuracy of solid tumors.