Dual-targeting nanotheranostics for MRI-guided enhanced chemodynamic therapy of hepatoma via regulating the tumor microenvironment

Abstract

Chemodynamic therapy (CDT), as a reactive oxygen species (ROS)-based therapeutic modality, has attracted much attention in recent years. However, the insufficient therapeutic effect of CDT is due to the antioxidant system in the tumor microenvironment, such as high levels of glutathione (GSH). In this study, we developed a biological/physical dual-targeting nanotheranostic agent (relaxation rate, r₁: 6.3 mM⁻¹ s⁻¹ and r₂: 13.11 mM⁻¹ s⁻¹) for enhanced CDT of SMCC-7721 tumors. This nanotheranostic agent is composed of a homologous tumor cell membrane (TCM), magnetic ferric oxide, and manganese oxide and is denoted as FM@TCM nanoparticles (NPs). A favorable effect of in vitro CDT on SMCC-7721 cells (IC₅₀: 20 μg mL⁻¹) is demonstrated, attributed to the Fenton reaction and oxidative stress resulting from the reduction of the GSH level. In vivo T1/T2 magnetic resonance imaging (MRI) confirms that the tumor accumulation of FM@TCM NPs is promoted by concurrent bioactive targeting of the homologous TCM and physico-magnetic targeting of tumor tissues with an external magnetic field. Impressive chemodynamic therapeutic effects on SMCC-7721 tumors are demonstrated through the catalysis of endogenous hydrogen peroxide and depletion of GSH to generate high levels of ROS. Dual-targeting FM@TCM NPs inhibit SMCC-7721 tumor growth (∼90.9%) in vivo without any biotoxicity. This nanotheranostic agent has great potential for use in MRI-guided CDT.