Research On Preparation And Application Of Combined Therapeutic Near-Infrared-Ⅱ Fluorescent Probe

Even in today’s highly developed modern medicine,cancer is often a major disease with no solution,especially the three common solid malignancies:lung cancer,liver cancer and gastric cancer do not have any universal specific drugs.Serious threat to people’s healthy life.Therefore,research on tumor diagnosis,treatment and postoperative rehabilitation is still very important and meaningful.For tumor diagnosis,fluorescence imaging,especially the NIR-Ⅱ fluorescence imaging developed in recent years,has the characteristics of low biological tissue absorption,strong penetration and high resolution.It has been applied in the clinical operation of liver cancer patients,and has made significant progress in performance compared with visible light and NIR-I fluorescence imaging:achieving detection of centimeter-level tissue,and imaging resolution of millimeter-level depth reaching micron-level and other excellent results;For tumor treatment,due to the construction and accumulation of anti-tumor chemotherapeutic drug molecular libraries,it is of great significance to improve traditional chemotherapy by constructing nano-drug delivery systems.The emerging phototherapy technology has already become a research hotspot due to its advantages of low toxicity,less side effects,and high patient acceptance.Therefore,in this thesis,two novel NIR-Ⅱ fluorescence imaging-guided tumor combination therapy probes are prepared based on diketopyrrolopyrrole（DPP）.The specific research contents are as follows:（1）This thesis designed and synthesized a small organic molecule DPP-BT-TPA based on diketopyrrolopyrrole（DPP）for the first time.A single-laser-triggered optical diagnosis and treatment platform was prepared by co-encapsulating DPP-BT-TPA with the redox prodrug Camptothecin-Combretastatin A4（CPT-ss-CA4）in amphiphilic polymer micelles.The obtained nanoparticles were able to achieve long blood circulation and high tumor accumulation of DPP-BT-TPA and CPT-ss-CA4,which were confirmed in NIR-Ⅱ fluorescence imaging in live mice.Glutathione（GSH）,the most abundant antioxidant in the tumor microenvironment,can be used to cleave prodrugs to release the chemotherapeutic drug CPT and the angiogenesis inhibitor CA4.The photothermal effect under laser irradiation can further accelerate this process.The enhanced antitumor efficacy of combined photothermal/chemo/angiogenesis therapy has also been validated in vivo.We believe that the obtained combined therapeutic platform of single-laser-triggered NIR-Ⅱ imaging and triple-modality therapy functions has great potential in cancer therapy.（2）This thesis develops nanoparticle BDP NPs for combined PTT/PDT therapy guided by 730 nm laser excitation NIR-Ⅱ imaging.First,the classical organic dye diketopyrrolopyrrole（DPP）,electron donor PM159 and 3,8-dibromo-1,10-phenanthroline were ternary copolymerized through Stille reaction to obtain DPP based conjugated polymer BDP with excellent photophysical properties.and then combined F-127 with BDP by nanoprecipitation method to prepare BDP NPs.BDP NPs have a high NIR-Ⅱ fluorescence quantum yield（0.62%in water）under 730 nm laser irradiation,and NIR-Ⅱ imaging of blood vessels and tumors in vivo has been successfully achieved based on this probe.In addition,BDP NPs possessed high photothermal conversion efficiency and ¹O₂ yield simultaneously under 730 nm laser irradiation,and had obvious lethality to tumor cells.