Abstract
As a recently discovered form of regulated cell death, ferroptosis has attracted much attention in the field cancer therapy. However, achieving considerably enhanced efficacy is often restricted by the overexpression of endogenous glutathione (GSH) in tumor microenvironment (TME). In this work, we report a ferroptosis-inducing strategy of GSH depletion and reactive oxygen species (ROS) generation based on a biodegradable copper-doped calcium phosphate (CaP) with L-buthionine sulfoximine (BSO) loading (denoted as BSO@CuCaP-LOD, BCCL). BCCL was conducted by a biomineralization approach using lactate oxidases (LOD) as a bio-template to obtain Cu-doped CaP nanoparticles. Then, BSO was loaded to form BCCL nanoparticles with pH-responsive biodegradability to endow controlled release of Cu2+ and BSO in response to acidic TME. Benefiting from the catalytic performance of LOD, BCCL efficiently depletes the level of lactate in tumor, which can generate endogenous H2O2 for subsequent Fenton-like reaction. The Cu2+ and BSO intracellular GSH depletion followed by GSH-mediated Cu2+/Cu+ conversion, leading to the inhibition of glutathione peroxidase 4 (GPX4) and generation of •OH radicals via Cu+-mediated Fenton-like reaction. BCCL confers enhanced ferroptosis induction via intracellular LOD-induced H2O2 production, BSO-mediated GSH depletion, and Cu+-mediated ROS generation, leading to cause effective ferroptotic cell damage. As verified by in vitro and in vivo assays, the designed BCCL nanoplatform is highly biocompatible and exhibits superior anticancer therapy on uterine cervical carcinoma U14 tumor xenografts. This study, therefore, provides a biocompatible therapeutic platform that modulating the TME to enable intensive ROS generating efficacy and GSH depleting performance, as well as provides an innovative paradigm for achieving effective ferroptosis-based cancer therapy.