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

Abstract

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 T 2 -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 hypoxiatargeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.

Recent advances in engineering iron oxide nanoparticles for effective magnetic resonance imaging

“…Compared to single IONP, assembled architecture shows remarkably increased T 2 contrast ability. Modifying nanoparticles with specific molecular have been proved to be an effective strategy to implement their self-assembly under stimuli [ 271 ]. This unique phenomenon provided opportunity for IONP to complete the conversion from single state to assembled state and achieve T 2 active MRI imaging.…”

Design of Magnetic Nanoplatforms for Cancer Theranostics

“…However, because fluorescent molecules can be designed to achieve highly specific responsiveness, fluorescence imaging is often used as an auxiliary imaging method for the magnetotheranostics nanoplatform to monitor its response behavior in the body. Zhou et al [ 109 ] designed a nanoplatform capable of detecting tumor hypoxic environment, composed of ultrasmall SPIONs and assembly–responsive fluorescent dyes (NBD), and used nitroimidazole derivatives as hypoxia–sensitive detectors. Zhou et al [ 97 ] designed a nano–platform capable of detecting the hypoxic environment of tumors, consisting of USION and assembly–responsive fluorescent dyes (NBD), and used nitroimidazole derivatives as hypoxia–sensitive detectors.…”

Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy

“…These systems use specific stimulus signals to promote the directional delivery of NPs to tumors and to boost the anticancer activities of NP-carried drugs ( 31 , 74 ). The signals can be tumor intrinsic, such as an increased glutamine level ( 75 ), a decreased pH value ( 76 ), and hypoxia ( 77 ), or tumor extrinsic, such as a light source ( 78 ), a heat source ( 79 ), a magnetic field ( 80 ), or ultrasound ( 81 ). Among them, light-responsive systems may be the most well-studied systems because they can be readily controlled in a spatiotemporal manner, resulting in directional transport, improved tumor penetration and distribution, and controlled release of NP-carried drugs.…”