Theranostic Nanomedicine for Synergistic Chemodynamic Therapy and Chemotherapy of Orthotopic Glioma

Glioma is a common primary brain malignancy with a poor prognosis. Chemotherapy is the first-line treatment for brain tumors but low efficiency of drugs in crossing the blood-brain barrier (BBB) and drug resistance related to tumor hypoxia thwart its efficacy. Herein, a theranostic nanodrug (iRPPA@TMZ/MnO) is developed by incorporating oleic acid-modified manganese oxide (MnO) and temozolomide (TMZ) into a polyethylene glycol-poly(2-(diisopropylamino)ethyl methacrylate-based polymeric micelle containing internalizing arginine-glycine-aspartic acid (iRGD). The presence of iRGD provides the nanodrug with a high capacity of crossing the BBB and penetrating the tumor tissue. After accumulation in glioma, the nanodrug responds to the tumor microenvironment to simultaneously release TMZ, Mn2+, and O-2. The released TMZ induces tumor cell apoptosis and the released Mn2+ causes intracellular oxidative stress that kill tumor cells via a Fenton-like reaction. The O-2 produced in situ alleviates tumor hypoxia and enhances the chemotherapy/chemodynamic therapeutic effects against glioma. The Mn2+ can also serve as a magnetic resonance imaging (MRI) contrast agent for tumor imaging during therapy. The study demonstrates the great potential of this multifunctional nanodrug for MRI-visible therapy of brain glioma.