Near-Infrared Phototherapeutic Agents Based On Aza-Boron-Dipyrromethene Derivatives:Design,Synthesis And Biological Applications

Phototherapy(PT),including photodynamic therapy(PDT)and photothermal therapy(PTT),has attracted extensive research interests owing to its non-invasiveness and timely manipulation.For PT,it is a key issue to develop highly efficient phototherapeutic agents(PTA)that can effectively cure tumor.However,up to now,most of the reported organic PTA suffered from poor stability and biocompatibility,low photothermal conversion and singlet oxygen generation performance,simple function and the lack of effective theoretical guidance.Thereby,it is very important to develop highly efficient organic PTA via a facile and rational design strategy following specific rules.With the above consideration,we chose aza-BODIPY dyes as the candidates,because of their intense near-infared absorption,excellent stability and easily modified chemical structures.And a series of highly efficient PTA based on aza-BODIPY dyes have been rationally designed and facilely synthesized via intramolecular photoinduced electron transfer(PeT)mechanism,heavy atom effect and perturbation theory.And the corresponding mechanisms are discussed in detail.Finally,under the guidance of imaging,PTA has successfully inhibited the growth of tumors.The main contents of thesis are shown as below: 1.The design and synthesis of photothermal agent based on intramolecular photoinduced electron transfer for biological applicationThe efficient photothermal agent A-1,combining dimethylamine moiety and the aza-BODIPY skeleton,was rationally constructed by utilizing an intramolecular photoinduced electron transfer mechanism.The existence of intramolecular PeT process in A-1 and its important role to improve photothermal effect have been demonstrated by theoretical calculation and steady-state and time-resolved photoluminescence(TRPL)spectra.After encapsulation by polymer,A-1 NPs showed excellent photothermal conversion(35.0%)and concentration-dependent photoacoustic performance.Finally,A-1 NPs could successfully inhibit the growth of tumors by photoacoustic and photothermal imaging guided photothermal therapy.Therefore,this reasonable design via intramolecular PeT offers guidance to construct other excellent photothermal agents and subsequently may provide a new opportunity for future clinical cancer treatment.2.The design and synthesis of phototherapeutic agent based on intramolecular photoinduced electron transfer and heavy atom effect for biological applicationThe highly efficient phototherapeutic agent B-3 with enhanced photothermal conversion and singlet oxygyen generation capacities,combining alkylamine moiety,halogen atoms and the aza-BODIPY skeleton,was rationally constructed by utilizing an intramolecular PeT mechanism and heavy atom effect.Heavy atom effect contributed to boost photothermal conversion and singlet oxygen generation performance of aza-BODIPY skeleton.Intramolecular PeT helped to enhance the photothermal conversion and red-shifted absorption of aza-BODIPY skeleton.After encapsulation by polymer,B-3 NPs showed the high photothermal conversion performance(43.0%),and the excellent photothermal and reactive oxygen and nitrogen species(RONS)resistance.Finally,B-3 NPs successfully inhibit the growth of tumors by utilizing their excellent photothermal conversion and singlet oxygen generation capacity under the guidance of bioimaging.The exploration elaborates the photothermal conversion and singlet oxygen generation mechanism of small organic compounds and provides a guidance to develop excellent multifunctional NIR phototherapeutic agents for the promising clinical applications.3.The design and synthesis of phototherapeutic agent based on perturbation theory for biological applicationUnder the guidance of perturbation theory,highly efficient phototherapeutic agent C-4 was rationally designed and facilly synthesized by combining thienyl rings,halogen atoms and the aza-BODIPY skeleton.Theoretical calculations and photophysical characteristics validated that the enhanced intersystem crossing rate for singlet oxygen generation and nonradiative transition for photothermal conversion efficiency can be realized simultaneously,through the rational optimization of donor–acceptor structure,heavy atom number and their functionalization position,which can effectively decrease energy gap between the singlet and triplet states and increase spin–orbit coupling constant.After encapsulation by polymer,C-4 NPs showed concentration-dependent photoacoustic,fluorescence and photothermal performance.Finally,C-4 NPs successfully cured tumors by multimode imaging guided synergistic photothermal and photodynamic therapy.Thus,this study elaborates the intrinsic mechanism of organic PTA and guides the rational design of more excellent organic PTA via perturbation theory.4.The design and synthesis of efficient phototherapeutic agent based on dual heavy atom effect for biological applicationAn efficient phototherapuetic agent D-I-P was rationally designed and synthesized based on azadipyrromethene derivatives by introducing platinum atom and iodine atoms to azadipyrromethene skeleton simultaneously.Photophysical characteristics validated the positive effect of platinum and iodine atoms on azadipyrromethene skeleton for the enhanced photothermal conversion and singlet oxygen generation performance simultaneously.Especially,the latter showed the better performance,and their combination displayed the synergistic results.After encapsulation by polymer,D-I-P NPs showed concentration-dependent photoacoustic and photothermal performance,and EPR effect.At last,D-I-P NPs with high photothermal conversion and singlet oxygen generation performance could effectively cure the tumors under imaging guidance.The work systematically expounds the positive effect of heavy atom on azadipyrromethene skeleton for the enhanced photothermal conversion and singlet oxygen generation performance and offers guidance to develop other novel phototherapeutic agents.