Copper Sulfide-based Multifunctional Nanomedicine For Tumor Combined Therapy

Tumor nano photothermal therapy uses photothermal agents to convert light into heat to achieve local heating and ablation of tumor cells,which has the advantages of minimally invasive,accurate and low side effects,and is considered to be one of the most potential tumor treatment options.Nano copper sulfide（Cu S）has the advantages of simple preparation method,low cost,good thermal stability and high photothermal conversion efficiency,and is a nano photothermal agent with great application potential.However,it is difficult to effectively inhibit tumor growth by photothermal therapy with nano-Cu S alone,and other treatment methods should be combined to further improve the tumor treatment effect.Therefore,two kinds of multifunctional nanomedicine based on Cu S nanoparticles,which are integrated with chemotherapy,photothermal therapy and chemodynamic therapy,were prepared to realize the combined treatment of tumors.It is mainly divided into the following two parts:In the first part,Cu S based multifunctional nanomedicine with surface functionalization of the ferrocene-grafted hyaluronic acid.Firstly,Cu S nanoparticles at10-20 nm were prepared and loaded together with doxorubicin（DOX）into phase change nanoparticles（PCM）modified withβ-cyclodextrin（β-CD）.Subsequently,the ferrocene-grafted hyaluronic acid（HA-Fc）was modified on the surface of nanoparticles byβ-CD/Fc host-guest interaction.Finally,multifunctional nanomedicine Cu S-DOX@PCM-CD@HA-Fc were obtained with a particle size of 179.4 nm,the loading rate of Cu S was2.41%,and the loading amount of DOX was 2.55%.The Fc involved Fenton reaction could achieve chemodynamic therapy.The photothermal properties,biocompatibility,tumor targeting and anti-tumor therapeutic effect of nanomedicine were studied.The results show that the prepared nanomedicine have ideal photothermal properties;the nanomedicine has no obvious toxicity to B 16 melanoma cells and L02 normal liver cells under dark conditions;the nanomedicine has targeting effect on CD44-overexpressed tumor cells;the combined chemotherapy/photothermal/chemodynamic function of nanomedicine was verified by cell experiments.The tumor targeting ability and the effect of combined chemotherapy/photothermal/chemodynamic therapy in vivo were studied by using B16 melanoma mouse model.Studies have shown that multifunctional nanomedicine can be targeted and enriched at the tumor site,and the tumor inhibition rate of mice can reach 83.3%through combined therapy.In the second part,H-Cu S based multifunctional nanomedicine with surface functionalization of the tannic acid-ferric chloride.Based on the previous part,hollow Cu S（H-Cu S）was used to directly load chemotherapy drugs and designed to further enhance the photothermal performance of Cu S.Firstly,H-Cu S nanoparticles with an average particle size of 196.1 nm were prepared,and loaded with chemotherapy drug camptothecin（CPT）,and then coated with tannic acid（TA）and ferric chloride（Fe Cl₃）on the surface of H-Cu S@CPT to prevent the leakage of CPT.The results show that H-Cu S@CPT@TA/Fe Cl₃ multifunctional nanomedicine with a particle size of 217nm and a loading capacity of 9.91%CPT were obtained.The photothermal capacity of TA/Fe Cl₃complexes can further enhance the photothermal effect of H-Cu S,and the Fe³⁺-involved Fenton reaction can achieve chemodynamic treatment.The photothermal properties,biocompatibility and anti-tumor therapeutic effect of nanomedicine were studied.The results show that the prepared nanomedicine has remarkable photothermal properties and photothermal promoting effect of CPT release;the nanomedicine has no obvious toxicity to MCF-7 human breast cancer cells and L02 human normal liver cells under dark conditions;The drug can be released in a photothermal response under 808nm laser irradiation,achieving a combination of chemotherapy/photothermal/chemodynamic therapy at the cellular level.