An efficient reactive oxygen species/reactive nitrogen species generator for dual imaging-guided orthotopic glioblastoma therapy through intrathecal delivery

The treatment of glioblastoma is still an enormous challenge in the clinic, and treatment based on reactive oxygen species (ROS) has exhibited good potential for its therapy. However, the weak toxicity and short lifetime (e.g., 1O2 10−6 s,·OH 10−2 s) as great obstacles of the ROS-based antitumor strategy, as well as the blood-brain barrier (BBB) obstruction of most drugs into the brain, have immensely constrained the therapeutic effect. Herein, we construct a novel theranostic nanoagent (GLIF) based on Gd2(WO4)3:Nd3+ nanoparticles loaded with ploy-L-arginine (PLA), indocyanine green (ICG), as well as lactoferrin (LF) to enable efficient low-dose drug therapy via ROS and reactive nitrogen species (RNS) using intrathecal injection. The PLA and ICG loading not only enhances GLIF’s ability to generate NO, inhibit cell migration and support ROS/RNS to kill tumors, but also produces ONOO- with greater toxicity and longer lifetime (10−2 s) than 1O2. Moreover, intrathecal injection is adopted to bypass the BBB and the modification of LF promotes accumulation in lesions, causing tremendous side effects with long blood circulation. The significant therapeutic effect of GLIF has been proved in vitro and in vivo and confirmed for the first time in glioblastoma. The excellent performances of GLIF as a second near-infrared fluorescence (NIR-II) and magnetic resonance (MR) imaging contrast agent for glioblastoma diagnosis at a lower injection dose also prove the superiority of intrathecal injection over intravenous injection. These findings show that GLIF has great potential for dual-modal imaging and effective therapy of glioblastoma by combining intrathecal injection and the new pathways of ROS/RNS.