Design And Synthesis Of Near-infrared BODIPY Theranostic Agents For Excited-state Dynamics Behavior Research And Theranostic Applications

Boron-dipyrromryhene(BODIPY)as a typical organic fluorescent dye featured with high molar extinction coefficient,high photostability and easy modification has been widely applied in optical diagnosis and treatment.However,the designs of many existing theranostic agents are mainly focus on the modulation of photophysical property based on the structure manipulation,which is somewhat blindness without enough theoretical guidance.How to exploit and construct more new-type and high performance BODIPY optotheranostic agents has become a problem demanding prompt solution.In fact,as the cornerstone for exploiting more high-performance theranostic agents,in-depth excited-state dynamics behaviors research fundamentally uncover the photophysics process guiding the high-efficiency molecular construction.Ultrafast transient absorption spectroscopy technology as one of the most cutting-edge spectral analysis techniques can capture and record these photophysics processes,which make it possible to decipher these photophysics processe.The in-depth investigations of structure-performances relationship from the perspective of molecular excited-state dynamics can well guide material design optimization and performance improvement at the molecular level,meanwhile,facilitate the establishment of novel principles and methods to guideline optotheranostic material design optimization and performance enhancement.Therefore,this thesis takes BODIPY organic small-molecular as the research object and develops several near-infrared excited photosensitizers.Moreover,we introduce excited-state dynamics to biophotonics research pioneeringly,decipher the structure-performances relationship from the perspective of molecular excited-state dynamics and validate the potential in vivo bioapplications in biological imaging and cancer therapy.1.Deciphering the intersystem crossing in nearinfrared BODIPY photosensitizers for highly efficient photodynamic therapyWe synthesized an organic small-molecule photosensitizer based on BODIPY structure for highly efficient photodynamic therapy.As compared with the parent near-infrared BDP(?_?=?1%),2I-BDP exhibited an outstanding singlet oxygen quantum yield owing to the iodine-induced heavy atom effect which facilitated singlet-to-triplet intersystem crossing(ISC).More importantly,the ultrafast femtosecond transient absorption(fs-TA)spectroscopy was utilized to verify that 2I-BDP possessed an exceptionally enhanced ISC efficiency(?_ISC=91%).Moreover,quantum theoretical computation results further demonstrate multi-channel yet remarkably efficient ISC process in 2I-BDP,providing an in-depth understanding of ISC dynamics in organic near-infrared materials.Meanwhile,the PDT efficiency of 2I-BDP was valided in the in vitro and in vivo experiments.The results show high phototoxicity of 2I-BDP toward MCF-7 cells and the tumor volume of 2I-BDP injected mice was significantly inhibited under ultralow near-infrared light power-density(10 mW cm^-2).This work may set a valuable guidance in the designing of high-performing organic theranostic materials to boost the clinical cancer treatment.2.Manipulating nonradiative decay channel by intermolecular charge transfer for exceptionally improved photothermal conversionWe reported an in-depth study of nonradiative decay(NR)decay process in NIR BODIPY(BDP)dye.First,we synthesized BDP with intense NIR absorption(molar extinction coefficient,?10⁵ M^-1cm^-1)based on D-A structure.Furthermore,DSPE-m PEG5000 was used as organic matrix to encapsulate BDP to obtain water-soluble and biocompatible BDP nanoparticles(BDP NPs)through nanoprecipitation method.The photothermal experiment showed that BDP NPs displayed higher photothermal conversion efficiency than BDP.Femtosecond transient absorption(fs-TA)spectroscopy clearly revealed a totally different excited state dynamics behaviors within BODIPY monomer(BDP dye)and aggregates(BDP NPs),indicating strongly morphology dependent character.fs-TA spectra of the BDP NPs at different decay times displayed the occurrence of new excited-state absorption(ESA)species.Combining with quantum chemical calculation,this new ESA species can be attributed to the aggregation-stabilized intermolecular charge transfer(CT)state.Kinetic decay curves of GSB demonstrated the faster photoexcited population decays to S_0.Notably,the ultrafast NR channel(1.7 ps)in BDP NPs depleted a substantial portion of the excited-state population(71%),which accounted for its much better photothermal effect((?=61%))as comparing with the isolated BDP dye.Meanwhile,BDP NPs display a highly efficient photoacoustic imaging(PAI)guided photothermal therapy(PTT)of tumors in live mice.3.Enhancing the mechanistic insights of NIR-? emisssion in Aza-BODIPY dye for in vivo fluorescence imagingThis study introduces NIR-? Aza-BODIPY Dye for in vivo fluorescence imaging.We construct T-BDP by introducing electron-rich thiophene substituent(3 and 5positions)incorporating strong electron-donating groups,4-(N,N-dimethylamino)phenyl(1 and 7 positions),to the conventional Aza-BODIPY structure.Combining with the strong electron-withdrawing nature of borane difluoride azadipyrromethene's center,T-BDP with a D-A-D structure favored bathochromic shift in NIR-? region.Through solvatochromic experiments and quantum chemical calculations,up to 8.2%fluorescence quantum yield for T-BDP is ascribed to the formation of hybridized local and charge transfer(HLCT)state.Femtosecond transient absorption(fs-TA)spectra clearly presents the ultrafast charge transfer(CT,1.7 ps)from locally excited(LE)state to CT state,both of which contribute the NIR-? emission from LE state(115 ps)and CT state(353 ps),paving insightful mechanic understanding of NIR-? emission.Moreover,Pluronic F-127 was used as organic matrix to encapsulate T-BDP to obtain water-soluble and biocompatible T-BDP nanoparticles(T-BDP NPs)through nanoprecipitation method.However,the compact nanostructure causes the decline of fluorescence quantum efficiency as compared of dispersed T-BDP fluorophores.As for aggregated T-BDP,nonradiative intermolecular CT state that caused by aggregation dominates the substantial nonradiative depopulation to generate superior photothermal effects.Meanwhile,less population of S₁ return back to S₀ via traditional S₁?S₀ emission and IC(nonradiative decay).Nevertheless,the nanosized T-BDP preferred passive-targeting ability,and good water-solubility for in vivo NIR-? fluorescence imaging.