Preparation,structure-activity Relationship And Photodynamic/photothermal Therapy Of Pyridinium Salts And Cyaninium Salts Photosensitizers/photothermal Agent

Fluorescence imaging-guided photodynamic/photothermal therapy is a new cancer treatment method in recent years.This method of cancer treatment has significant advantages in accurately showing the location of photosensitizer/photothermal agent in tumor tissue and noninvasive reliable treatment.Among them,how to develop an excellent photosensitizer/photothermal agent is the focus of the method.In this paper,a series of novel pyridinium and cyanine-based photosensitizers/photothermal agents were designed and synthesized for fluorescence imaging-guided photodynamic/photothermal therapy.Futhermore,those photosensitizers could realize real-time monitoring of cell activity and microenvironment changes.1.Triphenylamine and pyridine salt with different alkyl chain lengths were choosen as electron donor and electron acceptor,respectively.A series of AIE photosensitizers TL1C-TL8C were obtained through Knoevenagel reaction and characterized by ¹H NMR spectrum,¹³C NMR spectrum and mass spectrum.Mitochondrial co-localization experiments showed that with the extension of the tail alkyl chain of triphenylamine pyridine salt,the photosensitizer could target mitochondria more accurately.Water/octanol partition coefficient experiments showed that the extension of alkyl chain increased the lipophilicity of the photosensitizer TL1C-TL8C gradually,which increased the interaction between photosensitizer and mitochondrial phospholipid bilayer so that the molecule could target mitochondria accurately.The singlet oxygen experiment showed that TL8C with longer alkyl chain had higher singlet oxygen production rate compared with TL1C-TL6C,which provided the possibility for the realization of cell photodynamic therapy.The in vitro cell assay showed that TL8C was highly effective in killing cancer cells under light illumination.In addition,TL8C could cause mitochondrial autophagy and gradually target autophagy vacuoles upon light illumination,realizing mitochondrial autophagy tracking successfully.2.Based on literature research,in order to improve the singlet oxygen yield,we introduced an extra benzene ring between triphenylamine and pyridine salt to obtain photosensitizer（E）-4-（2-（4’-（diphenyl amino）-[1,1’-biphenyl]-4-base）vinyl）-1-methyl pyridine-1-ammonium iodide（Mito-I）with longer conjugate length.Compared with（E）-4-（4-（diphenylamino）styrene）-1-methylpyridine-1-ammonium iodide（TP-I）,the introduction of benzene ring promoted the electron separation of the highest occupied molecular orbital（HOMO）and the lowest unoccupied molecular orbital（LUMO）,improving the singlet oxygen generation efficiency of Mito-I.In addition,Mito-I could target mitochondria and generate singlet oxygen efficiently,which provided the possibility of realizing photodynamic therapy with mitochondria targeting.At the same time,Mito-I possessed a highly selective and sensitive fluorescence response to viscosity,which could track the dynamic changes of mitochondrial viscosity during autophagy in real time.This study provides a reference for the monitoring the mitochondrial microenvironment and photodynamic therapy simultaneously3.A NIR-I emitted photosensitizer probe HI-Br was reasonably designed and synthesized to solve the problem of poor optical band and weak penetration of traditional photosensitizers.Through electron spin resonance spectroscopy（ESR）experiment,we proved that HI-Br can produce superoxide anion(O₂^-·)under light induction and realize type I photodynamic therapy,which could solve the adverse effects of tumor hypoxia on traditional photosensitizers.At the same time,the excellent photothermal properties of HI-Br enabled it to realize the combination of photodynamic therapy and photothermal therapy,which improved the therapeutic effect of photosensitizer.