Syntheses Of Novel BODIPY-based Sensitizers And Their Applications In Photodynaminc Therapy

Photodynamic therapy(PDT)has attracted considerable attentions recently because of high spatiotemporal resolution,significant inhibition for kinds of cancers and low drug resistance.However,the clinical existing photosensitizers in PDT often present weak absorption in near infrared(NIR)window,low singlet oxygen generation efficiency and non-specific tumor targeting property.The thesis focuses on how to enhance the absorption intensity of photosensitizers in NIR,boost the singlet oxygen generation efficiency,improve the tumor targeting and enrich the types of photosensitizers.(1)The absorbance of C60 was enhanced in visible region and singlet oxygen generation efficiency of C60 was improved by resonance energy transfer mechanism(RET).In Dyad-1,Dyad-2 and Triad-1,BODIPY fluorophores were light antenna to absorb visible light.C60 was used as triplet state "spin converter";C60 and BODIPY fluorophores were conjugated.The BODIPY moiety transfer excited energy to C60 moiety.C60 induced the BODIPY generated triplet excited state distribution.The new C60-BODIPY sensitizers have intense absorption and high singlet oxygen quantum yield in visible region.The kinds of sensitizers have the potential in PDT application.In addition,ulitilization 4-N,N-dimethylamin-styryl-BODIPY as light antenna,the triplet excited state properties of C60-BODIPY(Dyad-3 and Triad-2)were modulated by acid.Intramolecular charge separated state(C60-BODIPY+)can from 4-N,N-dimethylamin-styryl-BODIPY to C60 quench the triplet excited state for the photosensitizers(Dyad-3 and Triad-2).After the protonation of 4-N.N-dimethylamin-styryl-BODIPY,intramolecular charge separated state of C60-BODIPY was disappeared,resulted in long triplet excited lifetime and high singlet oxygen quantum yield for Dyad-3 and Triad-2.(2)Acid/thiols-sensitive photosensitizers were deigned and synthesized based on the weak acid and high redox species in tumor microenvironment.The absorption of 4-N,N-dimethylamin-styryl-diiodio-BODIPYwas broadened by RET.In acid condition,the photosensitizer(Dyad-4)had high singlet oxygen quantum yield,however,Dyad-4 did not efficiently generate singlet oxygen in neutral.By nanosecond transient absorption spectra analysis,intramolecular charge transfer(ICT)effect can efficiently modulate triplet excited state of Dyad-4 in polarity solvents.For Dyad-5,in the absence of thiols,upon photoexcited 2,6-diiodio-BODIPY moiety,resonance energy transfer from 2,6-diiodio-BODIPY moiety(donor)to DNS-styryl-BODIPY moiety(acceptor)competed with intersystem crossing of 2,6-diiodio-BODIPY so that 2,6-diiodio-BODIPY presented low singlet oxygen quantum yield.In Dyad-5,the triplet excited state located at DNS-styryl-BODIPY moiety beacuse T1 of DNS-styryl-BODIPY was lower than 2,6-diiodio-BODIPY.Additionly,Fluorescence of styryl-BODIPY was quenched by photoinduced electron transfer(PeT)from styryl-BODIPY to DNS.In the presence of thiols,resonance energy transfer effect was disappeared in Dyad-5 due to disulfide bond cleavage,resulted in the recovery of singlet oxygen quantum yield of 2,6-diiodio-BODIPY.Meanwhile,the strong electron withdrawing group of DNS was also cleaved by thiols so that the fluorescence of styryl-BODIPY significantly enhanced.Finally,Dyad-5 was used to fluorescence imagine guided photodynamic therapy in viro,and then Dyad-5 presented a good cancer cells inhibition with lower power LED irradiation.(3)Resonance energy transfer(RET)mechanism was proposed to broad the absorption intensity and singlet oxygen generation efficiency of BODIPY based photosensitizer in red region.Distyryl BODIPY(donor)and distyryl-diiodio-BODIPY(acceptor)chromophore were conjugated by click reaction.The new photosensitizer(RET-BDP)presented broad and intense absorption in red region.Singlet oxygen generation efficiency of RET-BDP improved 1.9 folds than clinical practice photosensitizer-Chlorin e6.With low power LED irradiation,RET-BDP not only can kill different types of cancer cells in vitro,but also can inhibit the growth of breast tumor in living mice.Besides,RET-BDP showed low physiological toxicity through pathologic analysis,so RET-BDP has potential for application in clinical transformation.(4)Carbazole substituted distyryl-2,6-diiodio-BODIPY(Car-BDP)was designed and synthesized,which showed intense absorption and high singlet oxygen quantum yield in NIR.Car-BDP was coated by amphiphilic PLA-PEG polymer via self-assembly to obtain uniform and ultra-small water-soluble nanoparticles(Car-BDP-TNM).Car-BDP-TNM not only exhibited good cancer cells inhibition in vitro,but also can efficiently restrain the growth of breast cancer in living mice in deep seats level.In addition,Car-BDP-TNM presented low physiological toxicity and was cleared from the body by liver system.