Molecule Design And Excited-state Regulation Of Cyanine-based Photosensitizer For PDT

Cyanine dyes are widely used in bioimaging and in vitro detection due to their excellent photophysics and easily modifiable structures.However,due to their structural limitations,cyanine dyes still suffer from poor stability,short triplet lifetime,low singlet oxygen quantum yield and lack of tumor targeting,which severely limits their clinical applications.There are few reports that comprehensively evaluate how to modify the structure of cyanine dyes to affect the efficacy of phototherapy.Hence,the application of new and efficient cyanine dye photosensitizers in photodynamic therapy still needs to be developed.Focusing on the design and development of high-performance cyanine dye photosensitizer,this thesis studied the molecular structure-activity relationship of cyanine dyes.Based on this,the application research of a variety of photosensitizers for photodynamic therapy is carried out,including long-wavelength aza-pentamethrine dye photosensitizers,conformation-limiting enhanced photosensitizers and dimer cyanine photosensitizers.The specific research contents are as follows:（1）Two near-infrared aza-pentamethine dye photosensitizers（BY-Br and BY-H）were constructed by azaindole instead of the common indole at both ends of the pentamethine dye.Compared with the indole pentamethanine dye Cy-H（651 nm）,the maximum absorption wavelengths of BY-Br and BY-H are red-shifted to 736 nm and 716 nm,respectively,which could achieve deeper tumor treatment.Meanwhile,the introduction of bromine atoms at the 5-position of azaindole of BY-Br has been enhanced reactive oxygen species（ROS）generation after laser irradiation.In vitro studies,BY-Br can achieve a good photodynamic therapy effect in MCF-7 cells under 730 nm light irradiation(IC₅₀ was 1.08μM).（2）A conformationally restricted hemicyanine photosensitizer CSZ-J was synthesized by a fusing polycyclic ring system to the polymethine chromophore strategy.The conformational restriction structure of CSZ-J greatly inhibits the nonradiative transition process,improving its fluorescence quantum yield and triplet quantum yield.The triplet quantum yield and the yield of reactive oxygen species were also greatly improved（ΦT of CSZ-J is 4.7 times that of ESZ-J）.CSZ-J can generate not only singlet oxygen through energy transfer,but also superoxide anion and hydroxyl radicals after illumination.This provides a new idea for the design of heavy-atom-free photosensitizers.In vitro cell experiments,CSZ-J exhibited high phototoxicity to tumor cells compared to ESZ-J and commercial Ce6.（3）A new series of dimer molecule based pentamethine cyanine dyes with different lengths of alkyl chains were designed and synthesized.The singlet oxygen quantum yield of dimers was increased due to the reduction of singlet-triplet energy gapsΔEST through intermolecular stacking of dimers.TheΦF and average fluorescence lifetime of dimers were regularly increased by lengthening the methylene chains and tended towards Cy-H.In addition,all dimer photosensitizers exhibit high molar extinction coefficients（1.5-2.0 times that of monomeric Cy-H）,high ¹O2 production（20-28 times that of monomeric Cy-H）,and excellent mitochondria-targeting capability in 4T1 cells.Among them,Cy-He-D has the longest triplet lifetime,low dark cytotoxicity,and high light cytotoxicity（IC50 is 0.92μM）.In vivo,dimer PSs have better enrichment and retention at tumor sites than monomeric Cy-H.The molecule Cy-He-D in 4T1 tumor-bearing mice can be well enriched and retained at the tumor site,and successfully inhibit tumor growth via photodynamic therapy.