Targeted Magnetic Resonance Imaging and Modulation of Hypoxia with Multifunctional Hyaluronic Acid-MnO2 Nanoparticles in Glioma

Manganese dioxide (MnO 2 )-based nanoparticles are a promising tumor microenvironment-responsive nanotheranostic carrier for targeted magnetic resonance imaging (MRI) and for alleviating tumor hypoxia. However, the complexity and potential toxicity of the present common synthesis methods limit their clinical application. Herein, multifunctional hyaluronic acid-MnO 2 nanoparticles (HA-MnO 2 NPs) are synthesized in a simple way by directly mixing sodium permanganate with HA aqueous solutions, which serve as both a reducing agent and a surface-coating material. The obtained HA-MnO 2 NPs show an improved water-dispersibility, fine colloidal stability, low toxicity, and responsiveness to the tumor microenvironment (high H 2 O 2 and high glutathione, low pH). After intravenous injection, HA-MnO 2 NPs exhibit a high imaging sensitivity for detecting rat intracranial glioma with MRI for a prolonged period of up to 3 d. These nanoparticles also effectively alleviate the tumor hypoxia in a rat model of intracranial glioma. The downregulation of VEGF and HIF-1α expression in intracranial glioma validates the sustained attenuation effect of HA-MnO 2 NPs on tumor hypoxia. These results show that HA-MnO 2 NPs can be used for sensitive, targeted MRI detection of gliomas and simultaneous attenuation of tumor hypoxia.