Design And Synthesis Of Novel AIE Photosensitizers And Its Application In Tumor Imaging And Therapy

Cancer,also known as malignant tumor,has become one of the leading causes of unnatural death in the global population,causing a heavy burden on the global economy and medical care.Common tumor treatments include surgery,chemotherapy and radiation therapy.Although these methods bring a chance of cure for cancer patients,there are also some side effects,such as the reduction of immunity caused by the trauma of surgery,which leads to inflammation and tumor recurrence and metastasis.Excessive use of drugs and X-rays can cause serious damage to normal tissue and other disadvantages.Therefore,the development of non-invasive,non-invasive and high spatial and temporal accuracy of new treatment methods is of great significance to improve the prognosis and improve the cure rate of tumors.Photodynamic therapy（PDT）,as a noninvasive and highly spatiotemporal selective method for tumor treatment,provides a new therapeutic method for precise treatment of tumor.However,PDT still has some problems.For example,photosensitizers（PSs）inactivation caused by aggregation induced quenching（ACQ）,the poor therapeutic effect caused by targeting without suborganelles,and the normal tissue damage caused by photosensitivity being"on"all the time.All these severely limit the therapeutic effect of PDT.Therefore,it is urgent to develop new PSs to solve these defects of the existing PDT.In view of the existing problems in the current PDT,based on the effect of aggregation-induced emission（AIE）,this paper designed and synthesized a variety of efficient PSs for specific imaging detection and precision therapy of tumors.The specific research contents mainly include the following three parts:（1）Because of its high selectivity to cancer cells and low toxicity to normal cells,activated PSs is very suitable for specific imaging and precise treatment of tumors.Furthermore,PSs that target important and vulnerable suborganelles are more effective at killing cancer cells.Based on this,we developed two new lysosomal p H-activated AIE PSs（N-3QL and N-3Meo QL）.The spectral properties and photosensitivity of the two PSs before and after protonation were simulated and calculated using density functional theory（DFT）,which provided theoretical support for the activation of PSs in the acidic environment of lysosomes.N-3QL and N-3Meo QL have a good targeting effect on lysosomes of cancer cells,and both p Ka are around 5.40,which can realize the photosensitivity of lysosomes activation in situ and generate toxic singlet oxygen（¹O₂）,so as to achieve the purpose of lysosome p H imaging detection and killing cancer cells.（2）Cancer cells and their mitochondria have more negative membrane potential,and positively charged molecules tend to enter cancer cells with more negative membrane potential and accumulate on the mitochondrial membrane.Based on this characteristic,we constructed an AIE-type PSs（TPE-4QL⁺）with strong positive charge for PDT targeting cancer cells and mitochondria to improve tumor therapeutic performance.TPE-4QL⁺has no obvious killing effect on normal cells due to its strong positivity,but can specifically target the mitochondria of cancer cells,thus realizing the specific recognition of cancer cells.In addition,the four quinoline salt functional groups in the molecular structure endow TPE-4QL⁺with a multiple twisted electron acceptor-donor-acceptor（A-D-A）structure,enabling a higher intersystem crossing（ISC）rate,which further improves the photosensitivity.It was proved that TPE-4QL⁺can realize the specific recognition of cancer cells in tumor bearing mice,thereby achieving remarkable therapeutic effect.（3）Cancer cells often contain abnormal expression of specific proteases（such as monoamine oxidase A）,and enzyme-activated PSs have better selectivity and biological responsiveness.Based on this,we developed a PSs probe（TPE-TTh Py）for highly specific activation of monoamine oxidase A（MAO-A）.We calculated the reasonable structure of TPE-TTh Py through DFT calculation and molecular docking simulation,the reasonable structure of TPE-TTHPY was designed,and TPE-TTh Py was synthesized and verified that TPE-TTh Py could only be activated by tumors overexpressed by MAO-A,and then transformed into TPE-TPYS,an AIE-type photosensitized molecule with D-π-A structure.At this time,ultraviolet absorption and fluorescence emission would be greatly red shifted.At the same time,the photosensitivity changes from"0"to"1",so as to achieve high specificity imaging detection and accurate treatment of tumors.