Self-Amplification of Oxidative Stress with Tumor Microenvironment-Activatable Iron-Doped Nanoplatform for Targeting Hepatocellular Carcinoma Synergistic Cascade Therapy and Diagnosis

Abstract Background The rapid development of hepatocellular carcinoma (HCC) treatment resistance has become a technical bottleneck for clinical treatment. Conventional chemotherapy has long been regarded as ineffective against HCC because of the insensitivity to chemotherapy drugs. Ferroptosis is a form of programmed cell death with a definite Fenton reaction mechanism that converts endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH). Therefore, we have developed an ultrasensitive iron-doped magnetic mesoporous silica nanoplatform (DOX@Fe-HMON-Tf NPs) for HCC-targeted synergistic cascade therapy and diagnosis. Results This organic/inorganic nanoplatform consists of a silica shell doped with iron and bis[3-(triethoxysilyl)propyl]tetrasulfide (BTES) and the etched core loaded DOX that generate H2O2 in situ to enhance the ferroptosis effect. DOX@Fe-HMON-Tf NPs can efectively internalized into hepatoma cells by precise delivery through the transferrin grafted with polyethylene glycol (PEG) outside the shell. The resulting nanoplatform can be activated by the tumor microenvironment (TME) in which the glutathione (GSH)-responsive biodegradability could synergize with the therapeutic interaction between DOX and iron and induce tumor cells death through complementary ferroptosis and apoptosis mechanisms. At the same time, the nanoplatform has a superparamagnetic framework that can be used for treatment guidance and monitoring under the guidance of T2-weighted magnetic resonance imaging (MRI). Conclusion The rationally designed nanoplatform provides a new strategy for anti-tumor effects with self-amplified synergistic chemotherapy and chemodynamic therapy (CDT) based on ferroptosis, and magnetic resonance imaging that realizes the integration of diagnosis, treatment and monitoring.