Design,Synthesis And Antitumor Activities Of Bodipy-based Nano-photosensitizers

Phototherapy is a new method of cancer treatment developed in recent years.It mainly includes photodynamic and photothermal therapy.It has the advantages of high efficiency,low toxicity,low invasiveness,and good targeting.Photosensitizer,light and oxygen in tissues are three elements of photodynamic therapy.The key substance is the photosensitizer.The properties of photosensitizers highly affect the efficacy of photodynamic therapy.Boron dipyrromethene(Bodipy)has high molar extinction coefficient,which can produce high singlet oxygen quantum yield or photothermal conversion efficiency by structural modification for tumor photodynamic/photothermal synergistic therapy.Therefore,they attract increasing attention in the field of photodynamic and photothermal therapy in recent years.In this thesis,Bodipy is encapsulated by the amphiphilic polymer PEG114-b-PCL60 to construct the corresponding nano-sized micelles.On the one hand,the tumor-targeting of the photosensitizer is improved.On the other hand,the degree of aggregation and the form of light conversion of the Bodipy molecules are regulated by controlling the drug loading,so that the maximum absorption peak is red-shifted to the ideal therapeutic window.The therapeutic effects are improved by photodynamic and photothermal synergistic effect.The contents of this thesis are summarized as follows:Chapter 1: Introduces the present situation of tumor and the common treatment methods.The photo-physical mechanism,the principle and application of photodynamic and photothermal therapy,the development of photosensitizers and the application of Bodipy-based photosensitizers are expounded.According to the background,the basis of this thesis is clarified.Chapter 2: Reports the preparation and characterization of nano-sized micelles by encapsulating Bodipy with the amphiphilic polymer PEG114-b-PCL60.The degree of aggregation and the form of light conversion of the Bodipy molecules are regulated by controlling the drug loading.The photo-physical and chemical properties are studied in details,including UV absorption,fluorescence emission,singlet oxygen generation and photothermal effect.The results show that the Bodipy molecules are arranged in the hydrophobic core of the micelles in J-type and H-type aggregated form.With the increase of drug loading,the aggregation degree increases,the maximum absorption is significantly red-shifted,the fluorescence intensity and quantum yield gradually decrease,radiation transition probability decreases,intersystem crossing and/or non-radiation transition probability increase,and then singlet oxygen production capacity and photothermal conversion effect are enhanced.Chapter 3: Describes the photodynamic and photothermal effects of Bodipy micelles at the drug loading level of 20% in tumor cells by using two excitation wavelengths of 660 and 785 nm.The main experiments include cellular uptake,subcellular localization,AO staining,cytotoxicity and cell death mechanism.The results show that Micelles can enter cells and locate in lysosome,and exhibit obvious photodynamic/photothermal synergistic effects under illumination.When using 660 nm light for phototherapy,the photodynamic effect contributes more to cytotoxicity.The contribution of photodynamic and photothermal effects are comparable under 785 nm illumination.Chapter 4: Describes the activity of Bodipy micelles at the drug loading level of 20% in animals by using two excitation wavelengths of 660 and 785 nm,including tissue distribution,production of single state oxygen in tumor sites,photothermal conversion effect and tumor inhibition effect.The results show that Micelles have good tumor accumulation ability.Under irradiation by 660 and 785 nm,tumor tissues suffer serious damage.Near-infrared 785 nm laser has a stronger penetration to tissues and induces a better anti-tumor effect.