Hypoxia-Triggered Self-Assembly of Ultrasmall Iron Oxide Nanoparticles to Amplify the Imaging Signal of a Tumor.


Zhou H(1)(2), Guo M(1)(3), Li J(1)(2), Qin F(1), Wang Y(1), Liu T(1), Liu J(1), Sabet ZF(1)(3), Wang Y(1)(2)(4), Liu Y(1)(2)(4), Huo Q(5), Chen C(1)(3)(2)(4).
Author information:
(1)CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, People's Republic of China.
(2)Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing 100021, People's Republic of China.
(3)University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
(4)GBA Research Innovation Institute for Nanotechnology, Guangdong 510700, People's Republic of China.
(5)Department of Biomedical, College of Biochemical Engineering, Beijing Union University, Beijing 100023, People's Republic of China.


Hypoxia is a common phenomenon among most solid tumors that significantly influences tumor response toward chemo- and radiotherapy. Understanding the distribution and extent of tumor hypoxia in patients will be very important to provide personalized therapies in the clinic. Without sufficient vessels, however, traditional contrast agents for clinical imaging techniques will have difficulty in accumulating in the hypoxic region of solid tumors, thus challenging the detection of hypoxia in vivo. To overcome this problem, herein we develop a novel hypoxia imaging probe, consisting of a hypoxia-triggered self-assembling ultrasmall iron oxide (UIO) nanoparticle and assembly-responding fluorescence dyes (NBD), to provide dual-mode imaging in vivo. In this strategy, we have employed nitroimidazole derivatives as the hypoxia-sensitive moiety to construct intermolecular cross-linking of UIO nanoparticles under hypoxia, which irreversibly form larger nanoparticle assemblies. The hypoxia-triggered performance of UIO self-assembly not only amplifies its T2-weighted MRI signal but also promotes the fluorescence intensity of NBD through its emerging hydrophobic environment incorporated into self-assemblies. In vivo results further confirm that our hypoxic imaging probe can display a prompt MRI signal for the tumor interior region, and its signal enhancement performs a long-term effective feature and gradually reaches 3.69 times amplification. Simultaneously, this probe also exhibits obvious green fluorescence in the hypoxic region of tumor sections. Accordingly, we also have developed a MRI difference value method to visualize the 3D distribution and describe the extent of the hypoxic tumor region within the whole bodies of mice. Due to its notable efficiency of penetration and accumulation inside a hypoxic tumor, our hypoxia imaging probe could also be considered as a potential candidate as a versatile platform for hypoxia-targeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.