Transition Metal-based Nanocatalytic Drug For Breast Cancer Theranostic

Breast cancer is the most frequent malignant tumor and the first leading cause of cancer-related death in women worldwide.The rapidly evolving nanocatalytic medicine that trigger specific Fenton reactions in the unique tumor microenvironment(TME)to convert the less toxic H2O2 into ·OH in situ may provide new possibilities to address breast cancer.Compared with reactive oxygen species(ROS)-based photodynamic therapy,sonodynamic therapy,and electrodynamic therapy,Fenton reaction-based chemodynamic therapy(CDT)has attracted increasing attention in metastatic breast cancer treatment owing to its high tumor specificity,noninvasiveness,and minimal side effects.However,most conventional CDT agents suffer from low catalytic activity since their catalytic active sites are confined to the superficial atoms,while inner metal atoms remain inert.Moreover,the weakly alkaline tumor intracellular pH(pHi≈7.2)and up-regulated antioxidant defense system restricted the Fenton-like reaction-mediated ·OH generation,which undoubtedly compromises the CDT efficiency.Additionally,a single-modal CDT is often difficult to completely inhibit the tumor growth due to the diversity of tumors.As a result,it is very important to improve the intratumoral Fenton reaction rate and design of potent CDT-based combinational therapy for promoting the development of CDT.In this study,we developed CDTchemotherapy nanosystem and CDT-photothermal therapy nanosystem,and their physicochemical properties,antitumoral efficiency,and biosafety were evaluated.Most of the Fe-based nanomaterials suffer from low catalytic efficiency due to its insufficient active site exposure and the relatively high tumor intracellular pH,which greatly imped its clinical application.Herein,macrophage membrane-camouflaged 4(2-aminoethyl)benzene sulfonamide(BS)-loaded hollow mesoporous ferric oxide(HMFe)nanocatalysts are designed to remodel tumor microenvironment with decreased intracellular pH for self-amplified CDT.As expected,the HMFe exhibited a stronger Fenton activity than that of solid Fe3O4,indicating that the increased specific surface area can significantly improve the catalytic efficiency.In vivo results indicated that the BS could induce intracellular H+accumulation for accelerating the ·OH generation,thereby triggering tumor cell apoptosis.Tumor-targeting evaluation revealed that the macrophage membrane-camouflaging endows the nanocatalysts with immune evading capability and improves tumoritropic accumulation by recognizing tumor endothelium and cancer cells through α4/VCAM-1 interaction.In addition,the HMFe can be employed to highly efficient magnetic resonance imaging to real-time monitor the agents’ bio-distribution and treatment progress.In vivo results well demonstrated that the nanocatalysts could realize self-amplified CDT and breast cancer metastasis inhibition via tumor microenvironment remodeling,which also provides a promising paradigm for improving CDT and antimetastatic treatment.To maximize the economical active-atom utilization and improve Fenton reaction rate,we prepared an ultrathin single-site bimetallic(Cu and Co)nanosheet(CuCo NS).The Cu atoms are coordinated with the N atoms of[Co(CN)6]linker,and isolated to each other due to the ultrahigh specific area of 2D nanomaterials,guaranteeing the active atom-economic utilization.It was also found that the CuCo NS exhibited superior Fenton-like activities and high photothermal conversion efficiency(PCE)(22.62%).Within tumor microenvironment,the CuCo NS can not only deplete tumoroverexpressed glutathione(GSH),but also could exert Fenton-like activity to produce·OH for CDT.More importantly,the GSH-depletion and ·OH-generation can be further enhanced by its photothermal effect,resulting in a large intracellular accumulation of·OH and lipid peroxides(LPO),which,in turn,could disrupt the heat shock proteins to attenuate the thermoresistance of tumor cells,thus leading to a mutually-reinforced PTT-CDT.Additionally,the high PCE and the presence of high-spin Cu/Co species allow CuCo NS as a photoacoustic/magnetic resonance imaging contrast agent to realtime monitor the agents’ bio-distribution and treatment progress.Both in vitro and in vivo experiments consistently confirmed that the mutually-reinforced PTT-CDT can significantly inhibit the tumor growth via a synergistic ferroptosis-apoptosis pathway.Therefore,this work pioneers a credible paradigm to integrate photothermal and Fenton-like activities into one nanoplatform through single-site dual-metal coordination strategy and provides an ideal candidate for achieving mutually-reinforced PTT-CDT.Overall,our study can be expected to provide a promising paradigm to overcome the practical obstacles associated with conventional CDT,and opens a new insight for development of theranostic CDT agents.