Synthesis Of Copper Sulfide Hollow Sphere-based Multifunctional Nanomaterials For Tumor Therapy

Cancer poses a serious threat to human health and safety.In recent years,a number of novel cancer treatment techniques have been developed,including photothermal therapy(PTT),photodynamic therapy(PDT),chemodynamic therapy(CDT),sonodynamic therapy(SDT),etc.,which has brought new directions for effective cancer treatment.Among them,PTT has the advantages of noninvasive,small side effects and high cure rate,attracted attention,etc.,its principle is as follows:when the tumor injected with photothermal agent(PTA)is enriched in the tumor site,and then irradiated by near infrared(NIR)light.PTA in the tumor area can absorb NIR light and convert it into heat,leading to the increase of tumor site temperature and the ablation of cancer cells.The key point of PTT is to develop photothermal agents with good photothermal performance.Copper sulfide(CuS)is one of the earliest inorganic semiconductor photothermal materials developed,,and has been a research hotspot in the field of PTT due to their advantages of simple preparation,low cost,good photothermal performance,etc..Although CuS have excellent application prospects in the field of cancer diagnosis and treatment,there are still some problems need to be solved:(1)Only one single photothermal therapy is less effective,and more treatment functions need to be combined to maximize its performance utilization.(2)The depth of tissue penetration of near infrared(NIR)laser is limited,lacks certain therapeutic effects on deep tumors;(3)Copper sulfide lacks clinical pre-treatment diagnosis and imaging functions,which limits its application in the integration of diagnosis and treatment.In order to solve these problems,we can optimize and develop multifunctional copper sulfide materials.The specific achievements of this paper are as follows:(1)Multifunctional DOX@H-Cu₉S₈/PEG Nanoplatform for Photothermally Augmented Chemo-Chemodynamic TherapyCuS has good photothermal performance,but the previous CuS does not have drug loading function,and the tumor treatment effect needs to be further improved.In order to solve the above problems,we have developed PEGylated Cu₉S₈ nanoparticles with the hollow spherical structure(H-Cu₉S₈/PEG),where Cu₉S₈ component simultaneously exhibits the photothermal and Fenton-like catalytic activity for PTT and CDT,and hollow structure can be used to load anticancer drugs for chemotherapy.The H-Cu₉S₈/PEG nanoparticles with a diameter of?100 nm have been synthesized by sulfurizing of Cu₂O nanoparticles through“Kirkendall effect”,and they exhibit high photothermal conversion efficiency of 40.9%.Meanwhile,H-Cu₉S₈/PEG nanoparticles are capable of Fenton-like reaction effect which can be further augmented(2 times that of without NIR)by photothermal effect.The hollow structure gives the H-Cu₉S₈/PEG high DOX loading capacity(21.1%),and then the DOX-releasing of DOX@H-Cu₉S₈/PEG can be furthered improved by p H and photothermal effect.When the DOX@H-Cu₉S₈/PEG dispersion is injected into tumor-bearing mice,the tumor growth can be efficiently inhibited due to the synergistic effect of photothermally-augmented CDT-chemo therapy.Therefore,the DOX@H-Cu₉S₈/PEG can serve as an“all-in-one”nanoplatform for imaging-guided synergistic treatment of malignant tumors.(2)Multifunctional HMME/CuS@MnO₂/PEG for MRI imaging-guided photothermal-sonodynamic combination therapy.CuS nanomaterials also lack the clinical medical imaging functions(such as magnetic resonance imaging(MRI)).In addition,NIR light used in PTT has a shallow penetration depth into biological tissues,limiting its further application.In order to endow CuS with clinical imaging function and realize tumor treatment at different depths,in this paper,MnO2 was grown on CuS hollow nanospheres by an ultrasonic reduction method,and the sonodynamic drug hemorpin monomethylether(HMME)was loaded inside CuS to obtain a HMME/CuS@MnO₂/PEG multifunctional nanoagent that integrates diagnosis and treatment.HMME/CuS@MnO₂/PEG nanoagent showed good MRI imaging and PTT-SDT synergistic effect.The material showed a high photothermal conversion efficiency(32.5%)under the stimulation of 1064 nm NIR light,and demonstrated good cytotoxic ROS production under US stimulation.After intravenous injection into the mice,the enrichment effect of the HMME/CuS@MnO₂/PEG at the tumor site could be monitored by MRI.Under the dual stimulation of NIR and US,multiple treatments showed good therapeutic effects.Therefore,HMME/CuS@MnO₂/PEG is expected to become an effective MRI imaging guided photothermal-sonodynamic tumor therapy nanoagent.