Preparation Of Copper Containing Composite Hydrogel And Anti-tumor Performance Of Copper Death Enhancement

One in six people will die of cancer,according to a recent World Health Organization report on cancer.Surgery,chemotherapy,and radiotherapy,etc.are currently the most common treatments for cancer.However,traditional treatments have shortcomings such as high risk,sereve side effects,and easy recurrence,making it difficult to achieve ideal cancer treatment outcomes.Therefore,it is necessary to explore new treatments.At present,people have successfully discovered new therapeutic methods,mainly including:photothermal therapy（PTT）,photodynamic therapy（PDT）,sonodynamic therapy（SDT）,chemodynamic therapy（CDT）,and gas therapy（GT）,etc.In a new treatment mode,nanomaterial-mediated PTT can precisely localise tumors by using external lasers to irradiate the focus area,thereby minimising the damage to surrounding normal tissue from the heat generated.However,a single PTT has the following drawbacks:firstly,the high temperature generated during the treatment process may stimulate the expression of heat shock proteins,and secondly,the penetration depth of the laser light is insufficient due to the large amount of scattering from biological tissues,which greatly reduces the treatment effect.The use of other therapies to enhance PTT may be an ideal direction for development.Currently,the main reported methods for improving PTT are SDT,which uses ultrasound as energy to focus sound energy on deep tissues without trauma,and can improve the shortcomings of insufficient penetration of PTT.Studies have shown that intracellular copper accumulation is a prerequisite for cell death,which is mainly involved in the tricarboxylic acid cycle of mitochondrial respiration.Therefore,combining copper death with PTT and SDT is an effective strategy to improve efficacy and reduce toxicity and side effects.Based on the above issues,two typesof copper-based nanoparticles have been prepared in this work:Cu-Co S_x and Cu/Zn-MOF-GOx-PDA（MGP）.These two nanomaterials are combined with hydrogels with good biocompatibility to prepare new nanoplatforms for combined treatment of tumors.The main research contents are as follows:（1）Firstly,Cu-Co S_x nanomaterials were prepared by solvothermal method.The test results show that the synthesized sample has high light absorption performance in the whole spectral range of 200-2500 nm.Under near-infrared laser irradiation,the photothermal conversion efficiency of its aqueous solution（0.125 mg/m L）reached22.8%.Secondly,hollow Cu/Zn-MOF was prepared by solvothermal method,and then glucose oxidase（GOx）and dopamine were sequentially loaded and coated on Cu/Zn-MOF to prepare MGP nanomaterials.The experimental results show that MGP nanomaterials irradiated by near-infrared lasers exhibit high photothermal conversion capabilities,with a photothermal conversion efficiency of 24.6%.Hydrogels have the advantages of easy access to raw materials,simple preparation methods,and response to stimulation.They are a good storage medium.Their three-dimensional network structure can accommodate a large number of water-soluble drugs.The composite hydrogels composed of Cu-Co S_x and MGP nanomaterials respectively and hydrogels have excellent porous structure and rheological properties,which are expected to achieve the controlled release of drug/gas molecules,thus helping to enhance the anti-tumor effect.（2）The synthesized Cu-Co S_x nanoflowers and doxorubicin hydrochloride（DOX）were added to sodium alginate hydrogels（SAHGs）to construct a novel type of Cu-Co S_x/DOX/SAHGs composite hydrogel for the synergistic treatment of PTT,SDT,GT,chemotherapy and copper death of tumors.The results showed that Cu-Co S_xnanoflower produced a large amount of singlet oxygen（¹O₂）under the dual action of near-infrared light and ultrasound,and could effectively inhibit the production of adenosine triphosphate（ATP）and the aggregation of dihydrolipoyl transacetylase（DLAT）,thus achieving the SDT and copper death of tumors;Cu-Co S_x/DOX/SAHGs have excellent photothermal properties under near-infrared light stimulation;the composite hydrogel realises the controllable release of H₂S and DOX under acidic conditions,and near-infrared light and ultrasound can promote the release of gas and DOX.In addition,Cu-Co S_x/DOX/SAHGs composite hydrogel can significantly inhibit the growth of tumor in mice under the action of near-infrared laser and ultrasound,thus realising the combined anti-tumor effect.（3）The injectable MGP/L-Arg/CS composite hydrogel was constructed by adding the prepared MGP nanomaterial and L-Arg to CS hydrogel.MGP nanoparticles can not only generate a large amount of reactive oxygen species（ROS）under the action of ultrasound,but also generate a large amount of NO gas in acidic environment through the addition of L-Arg composite hydrogel combined with near-infrared light and ultrasound,thereby realising SDT and GT;in addition,copper in MGP can enter cells and effectively inhibit ATP production under the intervention of near-infrared light and ultrasound,and can bind to dihydrolipoic acid transacetylase（DLTA）to induce copper death;MGP/L-Arg/CS injectable hydrogel has an ideal photothermal effect under near-infrared light;in addition,MGP/L-Arg/CS composite hydrogel has the ability to degrade glucose in the tumor microenvironment.The combined effect of near-infrared light and ultrasound can promote its degradation ability,thus achieving starvation treatment.Breast cancer bearing mice were selected as the research subjects.The injectable MGP/L-Arg/CS composite hydrogel showed significant synergistic anti-tumor effects on PTT,SDT,GT,starvation treatment and copper death under the action of near-infrared light and ultrasound.