Application Of Glutathione Responsive Ca(IO₃)₂@starch Nanoparticles In Photothermal Imaging/Therapy Of Tumor Cells

Photothermal therapy(PTT)is a new tumor therapy with the advantages of minimally invasive and high efficiency,which has great clinical application value.However,conventional PTT reagents present nonspecific distribution in tissues in vivo,which may cause damage to normal tissues during treatment.In addition,due to its own limitations,single photothermal therapy is difficult to achieve the best therapeutic effect.In order to solve these problems,we designed and developed a glutathione(GSH)-triggered PTT intelligent diagnostic reagent based on the special microenvironment of tumors,which not only significantly improved the signal-to-noise ratio of diagnosis,but also reduced the side effects on normal tissues.Subsequently,we further explored the synergistic treatment strategy of PTT combined with"calcium overload",which effectively improved the tumor immune microenvironment and enhanced the effect of immunotherapy.Specific work contents are as follows:Part ?:Study on the synthesis,properties and application of GSH responsive starch coated calcium iodate(Ca(IO₃)₂@starch)intelligent reagent in vivo imaging/therapy.Based on the principle that GSH can reduce iodate(IO₃^-)to iodine(I₂),and iodine(I₂)can combine with starch to form starch-iodine complex with near infrared absorption with starch,a starch-coated calcium iodate(Ca(IO₃)₂@starch intelligent diagnostic reagent was successfully prepared by us.The solution experiment shows that the near-infrared absorption of Ca(IO₃)₂@starch is very weak,and its photoacoustic imaging and photothermal therapy performance is poor.However,the starch-iodine complex can be formed rapidly after GSH triggering,which produces strong near-infrared absorption.The photoacoustic imaging performance and photothermal heating performance are improved by 21.5 times and 31.6 times,respectively.Subsequently,both in vitro and in vivo experiments have proved that the material has excellent biocompatibility.More importantly,the mouse tumor model proved that Ca(IO₃)₂@starch can be effectively triggered by GSH with high expression in tumors.Compared with normal tissues,the signal-to-noise ratio of tumor contrast was significantly improved,and the effect of PTT after triggering was very significant,with little injury to normal tissues.Part ?:Light and heat synergistic"calcium overload"improves tumor immune microenvironment and activates immune response.Based on the principle that light and heat can regulate calcium ion transport and effectively induce immunogenic death(ICD)of tumor cells,we further explored that Ca(IO₃)₂@starch can induce"calcium overload"of tumor cells,cooperate with PTT to improve tumor immune microenvironment and activate anti-tumor immune response in vivo.The solution and cell experiments showed that Ca(IO₃)₂@starch could release a large amount of Ca²⁺after GSH triggering.Under the action of light and heat,Ca²⁺could be induced to flow into the cell,causing"calcium overload"of tumor cells and causing tumor cell damage.At the same time,tumor cells release a large number of tumor antigen CRT,which induces the maturation of dendritic cells(DC)and enhances their antigen royalty ability.The mouse tumor model showed that in the treatment group,the contents of CD3⁺?CD4⁺and CD8⁺cells in spleen tissues of mice were significantly increased,and the infiltration of immune T cells in tumor tissues was also increased obviously.In addition to effective treatment for proximal tumors,the growth of distal tumors was also significantly inhibited.