Construction Of Novel Tumor Microenvironment-responsive Nanoprobes And Their Imaging Detection And Therapeutic Applications

Cancer has always been one of the main factors threatening human life,and human beings have been looking for methods of cancer diagnosis and treatment.Accurate tumor positioning is the key to efficient treatment.Fluoresce nce imaging has become one of the most commonly used methods for tumor imaging due to its high sensitivity,fast response speed,and simple operation.Of course,effective treatment of cancer is the decisive factor in achieving successful treatment of canc er.Chemodynamic therapy（CDT）is an effective tumor treatment strategy,which uses Fenton reaction between iron ion(Fe²⁺)and endogenous hydrogen peroxide（H₂O₂）in tumor cells,and the hydroxyl radical generated by the process has a killing effect on cancer cells,and its reaction product,hydroxyl radical（·OH）,has strong oxidizing properties.It can oxidize the biological macromolecules in cancer cells in situ,so it can produce strong damage to cancer cells,thereby achieving the goal of effective tumor therapy.Compared with photodynamic（PDT）therapy and photothermal therapy（PTT）that have emerged in the past few decades,CDT neither requires external light radiation,nor is affected by the local oxygen content.However,the inefficient Fenton reaction catalyst and the limited content of endogen ous H₂O₂ limit the application of CDT.In addition,many nano-reagents currently used for cancer diagnosis and treatment cannot"intelligently"identify cancer cells,resulting in greater t oxic side effects on normal tissue cells.Therefore,in order to so lve the above problems,this paper designed two nanoprobes with tumor microenvironment response characteristics and studied their applications in imaging detection and chemokinetic therapy.The two specific tasks carried out are as follows:1.In this chapter,we constructed a tumor targeting nanocomposites（CuNCs-Fe@HA）for cancer cell turn-on imaging and chemodynamic therapy.First,we synthesized copper nanoclusters（CuNCs）with tannic acid（TA）as stabilizer,and then coupled Fe³⁺to the nanoclusters through coordination action.However,due to the electron transfer process between CuNCs and Fe³⁺,the original fluorescence signal of CuNCs was quenched.The hyaluronic acid（HA）is finally coated on the outer layer of the nanocluster to form a fluorescence-free nanocomplex（CuNCs-Fe@HA）.Subsequently,due to the high expression of CD44 r eceptor content on the surface of tumor cells,after CuNCs-Fe@HA specifically enters the cancer cells through receptor-mediated effects,the over-expressed hyaluronidase in the cancer cells will digest the hyaluronic acid which on the outer layer of copper clusters.And then the over-expressed glutathione（GSH）in cancer cells reduces Fe³⁺to Fe²⁺,so that the fluorescence of the copper cluster is restored.At the same time,Fe²⁺reacts with the overexpressed H₂O₂ in cancer cells,producing highly toxic·OH,so as to achieve turn-on imaging and chemodynamic therapy of cancer cells.2.On the basis of the previous topic,we continue to develop nanoprobes that respond to the tumor microenvironment,we designed a new pH-responsive nanoplatform（CaO₂@TA-Fe（Ⅲ））for enhanced chemodynamic therapy.First,CaO₂nano-spherical aggregates were synthesized,an d then a dense（tannic acid）TA-Fe nano-coating was formed on the outer layer of CaO₂ nano-spherical aggregates.When the CaO₂@TA-Fe（Ⅲ）nanocomplex arrived at the tumor site,TA rapidly reduced Fe³⁺to Fe²⁺in the weakly acidic environment of the tumor,and the internal CaO₂nano-spherical aggregates hydrolyzed to produce H₂O₂,thus solving the two major shortcomings of CDT:（1）The catalyst efficiency of the Fenton reaction is low;（2）H₂O₂ content in cancer cells is insufficient.At the same time,the·OH produced by Fenton reaction between Fe²⁺and H₂O₂ puts tumor cells in the state of oxidative stress,which promotes the occurrence of“calcium overload”process,thus accelerating the death of tumor cells.The·OH generated based on the Fe³⁺mediated Fenton reaction promote each other with“calcium overload”process,greatly improving the therapeutic effect of tumor.