Hypoxia, a common phenomenon in solid tumors, plays an important role in the occurrence, progression, metastasis and therapy tolerance of tumors. Hypoxia has been employed as a single indicator of treatment prognosis.
The prediction and evaluation of hypoxia degree in tumor patients is significant to evaluate the therapeutic effect and selection of therapeutic modality. However, the hypoxic area is located far away from blood vessels in the tumor. Meanwhile, it is difficult for traditional contrast agents to enrich and stay in this area for a long time, which poses a great obstacle to the imaging of this area.
Prof. Chen's group and its collaborators have been committed to the basic and translational research of tumor hypoxia. They developed novel strategies to enhance the tumor permeability of nanoparticles and improve the efficacy of tumor diagnosis and treatment (Nano Today 2020, 34, 100907;Science Advance 2019, 5, eaax0937; Advanced Materials, 2020, 2006189; Angew Chem, 2020, 59: 14014-14018; Advanced Materials, 2016, 28, 8950).
Recently, researchers have designed the hypoxia-assembled iron oxide nanoparticles owning good tumor permeability and the ability to target hypoxia regions of the tumor. Those nanoparticles could effectively amplify tumor fluorescence and magnetic resonance imaging signals, providing a new method for the evaluation of tumors hypoxia.
Ultra-small iron oxide nanoparticles (UIO) are the preferred contrast agent for T2-weighted NMR imaging due to their advantages of uniform size, regular morphology, high safety and mature preparation methods.
In this study, nitroimidazole derivative (Pimo) was modified on the surface of UIO nanoparticles as a hypoxia trigger to construct the hypoxic probe UIO-Pimo. Ultra-small size can help UIO-Pimo penetrate into hypoxic areas of tumor.
At the same time, under the combination of hypoxic environment, electron donor and nitro reductase, Pimo performs biological reduction process, triggering the formation of large-size assemblies. This hypoxia-triggered UIO self-assemly strategy can greatly enhance T2 imaging signal, and improve the magnetic resonance imaging detection sensitivity of tumor hypoxia.
Meanwhile, MRI difference method was established to obtain the three-dimensional distribution of tumor hypoxia in vivo, which laid a foundation for the clinical application of this method. The UIO-Pimo probe also carries NBD molecules to enhance the fluorescence signal in hydrophobic environment, so that the assemblies realize enhanced fluorescence signal detection.
This hypoxic assembly strategy can greatly improve the concentration and retention of nanoparticles at the tumor site, and provide a new solution to overcome the therapeutic limitations caused by the limited penetration ability of nanomaterials.
This work was supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc.
Figure: Principle of the UIO nanoparticle self-assembly that amplifies the signal of MRI and fluorescence triggered by hypoxia.