Nanoscale Copper-Organic Complexes For Multi-Mode Targeted Tumor Therapy Via Two-Way Redox Dyshomeostasis

Redox homeostasis operating at a high level in tumor cells is an important feature of tumor microenvironment（TME）.Redox dyshomeostasis（RDH）can lead to the damage of biomolecules,and ultimately lead to tumor cell death.Therefore,redox homeostasis of tumor has become an attractive therapeutic target.Two-way RDH,which simultaneously increases the oxidizing substances and decreases the reducing substances in tumor cells,can induce RDH faster and to a higher degree than one-way RDH in tumor cells.What’s more,two-way RDH combined with other cancer therapy leads to better therapeutic effect.However,the current system for multi-mode cancer therapy based on two-way RDH is reported less and complicated to construct.Nanoscale metal-organic complexes（NMOCs）have great potential in construction of multi-modal tumor therapy system with the ability of two-way RDH due to their good biocompatibility,TME stimuli-responsiveness,diversity of organic ligands and metals,and ease of synthesis and modification.Based on this,by selecting reductive organic ligands with different function and Cu²⁺,two kinds of multi-functional NMOCs that can achieve two-way RDH were constructed and their antitumor effects were studied.The specific research results are as follows:1.Paramagnetic copper-organic frameworks for ferroptosis and magnetic hyperthermal combined therapy.Fc MOF was fabricated through the solvothermal method by using Cu²⁺and reductive Fc（COOH）₂.The results of scanning electron microscope（SEM）,transmission electron microscope（TEM）,specific surface area and porosity analysis（BET method）,X-ray photoelectron spectroscopy（XPS）,and Vibrating sample magnetometer showed that Fc MOF was uniform in size and its average size was 156 nm.It has porous structure formed by lamellar particles or layered structures,as well as paramagnetism,and contains Fc（COOH）₂,[Fc（COOH）₂]⁺,Cu⁺,and Cu²⁺.Lac-Fc MOF was obtained by Fc MOF being modified with lactose derivative（Lac-NH₂）that can target the asialoglycoprotein receptors overexpressed on Hep G2 cells.Studies showed that Lac-Fc MOF had good magnetic hyperthermia capability,hyperthermia stability,·OH production capacity,and GSH consumption capacity.In vitro experiments showed that Lac-Fc MOF could target and enter Hep G2 cells,then upregulate ROS level and consume GSH at the same time to achieve two-way RDH.The magnetic hyperthermal effect of Lac-Fc MOF under alternating magnetic field（AMF）can accelerate RDH to cause lipid peroxidation,the decreasing level of glutathione peroxidase 4,mitochondrion damage,and the decreasing level of adenosine triphosphate and heat shock proteins,which induces ferroptosis and makes Hep G2 cells more sensitive to heat.In vivo experiments of H22 tumor-bearing mice demonstrate that ferroptosis and MHT combined therapy based on two-way regulated RDH by Lac-Fc MOF show a significant antitumor effect.The results of cytotoxicity experiments and in vivo experiments proved that Lac-Fc MOF had good tumor inhibition effect,and the tumor inhibition efficiency was 90.4%.2.Methotrexate loaded histidine-copper NMOCs for DNA damage and repair inhibition-based cancer therpy.The NOMCs CuH was fabricated through the solvothermal method by using Cu²⁺and reductive L-histidine.The experimental results of SEM,TEM and XPS showed that CuH was irregular nanoparticle with the average size of 152 nm,and contained Cu²⁺and Cu⁺.HA-CuH@MTX was obtained by CuH loading with methotrexate（MTX）and then being modified with hyaluronic acid（HA）.Studies showed that the loading capacity of MTX in HA-CuH@MTX was 35.0%,the maximum release of MTX in the system containing 10 m M GSH within 72 h could achieve 85.6%,and HA-CuH@MTX could produce·OH and consume GSH.In vitro experiments showed that HA-CuH@MTX could enter the tumor cells in which it could consume GSH and upregulate ROS level to achieve two-way RDH which leads to DNA damage.The release of MTX and histidine could inhibit DNA repair to cause more severe DNA damage effect and inhibit tumor cell proliferation.In vivo experiments of 4T1 tumor-bearing mice proved that HA-CuH@MTX had good tumor inhibition effect,and the tumor inhibition efficiency was 83.6%.In conclusion,this paper constructed two kinds of multi-functional NMOCs that can achieve two-way regulated RDH by using reductive organic ligands with different functions and Cu²⁺,which provides new materials and strategies for two-way RDH-based multi-modal cancer therapy,and holds great potential in cancer therapy.