Hypoxia-Responsive T₂-to-T₁ Dynamically Switchable Extremely Small Iron Oxide Nanoparticles for Sensitive Tumor Imaging In Vivo

Abstract

To realize the accurate diagnosis of tumors by magnetic resonance imaging (MRI), switchable magnetic resonance contrast agents (CAs) between T1 and T2 contrast enhancement that are constructed based on extremely small iron oxide nanoparticles (ESIONPs) have been developed in recent years. We herein report, for the first time, a novel ESIONP-based nanocluster (named EAmP), which exhibited hypoxia responsiveness to the tumor microenvironment and offered a T2-to-T1-switchable contrast enhancement function, effectively distinguishing between the normal tissue and tumor tissue. In detail, active perfluorophenyl ester-modified ESIONPs with a diameter of approximately 3.6 nm were initially synthesized, and then 4,4′-azodianiline was used as a cross-linker to facilitate the formation of nanoclusters from ESIONPs through the reaction between the active ester and amine. Finally, poly(ethylene glycol) was further modified onto nanoclusters by utilizing the remaining active ester residues. The resulting EAmP demonstrated satisfactory colloidal stability and favorable biosafety and exhibited a desired T2-to-T1-switchable function, as evidenced by conversion from nanocluster to the dispersed state and a significant decrease in the r 2/r 1 ratio from 14.86 to 1.61 when exposed to a mimical hypoxic environment in the solution. Moreover, EAmP could decompose into dispersed ESIONPs at the tumor region, resulting in a switch from T2 to T1 contrast enhancement. This T2-to-T1-switchable contrast agent offers high sensitivity and signal-to-noise ratio to realize the accurate diagnosis of tumors. In conclusion, hypoxia-responsive EAmP is a potential MRI nanoprobe for improving the diagnostic accuracy of solid tumors.

A “Dual-Key-and-Lock” MRI Contrast Agent with T1–T2 Switchable Function for Accurate Diagnosis of Tumors

“…At present, various T 1 –T 2 and T 2 –T 1 switchable CAs have been developed for the diagnosis of brain diseases , and tumors. ,, For instance, Liu et al reported o-phenylenediamine and mannose-functionalized ESIONPs, which could assemble in response to the biomarker NO from the transition of M2 to M1 macrophages, offering insights into tumor macrophage M1/M2 polarization for precisely evaluating cancer prognosis . Moreover, previous work in our group utilized 4,4′-azodianiline as a cross-linker to obtain an ESIONP nanocluster (EAmP), which could respond to the tumor hypoxic microenvironment and decompose into dispersed ESIONPs, leading to a switch from T 2 to T 1 contrast enhancement for accurate tumor diagnosis . Nevertheless, all these T 1 –T 2 and T 2 –T 1 switchable CAs generally respond to a single biomarker stimulus, such as pH, glutathione (GSH), hypoxia, enzyme, and so forth.…”