Hypoxia-Responsive Aggregation of Iron Oxide Nanoparticles for T₁-to-T₂ Switchable Magnetic Resonance Imaging of Tumors

Abstract

Magnetic resonance imaging (MRI), one of the most general imaging techniques in the clinic, is widely employed for tumor diagnosis with the assistance of contrast agents (CAs). However, currently available CAs in the clinic suffer from shortcomings of a short blood circulation time, lack of specificity to pathological location, insufficient imaging window, and potential biotoxicity of the gadolinium ion. To overcome these problems, on the basis of extremely small iron oxide nanoparticles (ESIONPs), a hypoxia-responsive T1-to-T2 switchable MRI contrast agent was designed and constructed. In detail, polyacrylic acid-modified ESIONPs (ESIONPs-PAA) were first synthesized, and then, nitroimidazole derivatives and cysteine molecules were sequentially coupled on the surface of ESIONPs-PAA to obtain a hypoxia-responsive MRI contrast agent (HR-ESIONPs). Since 2-nitroimidazole and cysteine molecules on the surface of HR-ESIONPs can form an irreversible bond induced by the nitroreductase in the hypoxic tumor microenvironment, monodispersed HR-ESIONPs could transform into the nanocluster form, which can specially provide T2 contrast enhancement. In vitro experiments show that monodispersed HR-ESIONPs could effectively aggregate in the mimical hypoxic environment of tumors and switch from a T1 to T2 contrast agent. Moreover, in vivo experiments further confirm that HR-ESIONPs could effectively accumulate and realize the MRI signal switch from T1 to T2 contrast enhancement in tumors originating from the aggregation of HR-ESIONPs induced by the hypoxic environment, which promotes the diagnostic precision of tumors. Additionally, with the confirmation of favorable biosafety on cells and mice, hypoxia-responsive HR-ESIONPs are potential platforms to improve the diagnostic accuracy and sensitivity of MRI for tumors.

Multilayer Polymer Shell Perfluoropentane Nanodroplets for Multimodal Ultrasound, Magnetic Resonance, and Optoacoustic Imaging

“…Previously, the dependence of the T1 signal on the size of iron oxide nanoparticles has been demonstrated by several groups. [ 64 ] Positive T1 contrast is typically produced for ultrasmall iron oxide nanoparticles. However, even a slight aggregation leads to a drastic loss of this effect.…”

Molecular imaging of tumour‐associated pathological biomarkers with smart nanoprobe: From “Seeing” to “Measuring”

“…[68] Near recently, Pei et al synthesized the nitroimidazole derivatives and cysteine conjugated extremely small iron oxide nanoparticles, which can form nanocluster in the hypoxic tumour microenvironment, realizing the T 1 -T 2 switchable MRI of tumour. [69] In addition to the T 1 -T 2 switchable MRI nanoprobes, the T 2 -T 1 switchable nanoprobe can also be constructed based on the disaggregate of the superparamagnetic nanoparticles. Ling et al designed a pH-sensitive iron oxide nanoparticle assemblies cross-linked by aldehyde derivative crosslinkers.…”

Self‐Monitoring Theranostic Nanomaterials: Emerging Visual Agents for Real‐Time Monitoring of Tumor Treatment Processes

“…Although ESIONPs were not used for therapeutic monitoring in this study, it is possible to monitor the release of drugs through MRI mode switching by adding the drug between the NPs and the surface modifier. [93,94] In summary, while less controlled and personalized, TMEbased therapy and self-monitoring can achieve efficacy at deeper tissue sites with better precision. Examples of self-monitoring treatment by TME-responsive signals are summarized in Table 3.…”

“…Although ESIONPs were not used for therapeutic monitoring in this study, it is possible to monitor the release of drugs through MRI mode switching by adding the drug between the NPs and the surface modifier. [ 93,94 ]…”