Free-Radical Cascade Generated by AIPH/Fe₃O₄-Coloaded Nanoparticles Enhances MRI-Guided Chemo/Thermodynamic Hypoxic Tumor Therapy

Free radicals, including reactive oxygen species (ROS), play a critical role in determining cell's fate. When the level of free radicals is increased to a fatal value, it causes cancer cells to undergo senescence or cell death. Strategies that target this mechanism offer promising therapies against cancer. However, efficient and sustainable systems that generate free radicals, especially oxygen-independent systems, remain deficient. Herein, functionalized PLGA-based nanocomposites that efficiently co-deliver magnetic nanoparticles and 2,2'-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) were fabricated to achieve photothermal-induced thermodynamic therapy combined with macrophage polarization strategies; this therapy targets hypoxic tumors through the generation of an oxygen-independent free-radical cascade. These hybrid NPs can accumulate in the tumor microenvironment, and the encapsulated MNPs not only serve as contrast agents for enhanced magnetic resonance imaging but also exhibit the expected photothermal conversion and trigger the decomposition of AIPH to generate free radicals, thus causing cancer cell death. More importantly, the cell debris from apoptotic or necrotic cancer cells carries nondegraded MNPs, which can be endocytosed by recruited TAMs. MNPs can further induce TAMs to polarize to the M1 subtype to subsequently generate ROS. This study provides an alternative method for the generation of an oxygen-independent free-radical cascade for tumor co-therapy guided by magnetic resonance imaging PTT/TDT.