Molecular Design And Anti-Tumor Research Of Cyanine Dyes Based On Photoinduced Electron Transfer

As one of major applications of excited-state of functional dyes,photodynamic therapy（PDT）,a main element of phototheranostics,has been recognized as an emerging cancer treatment.However,current PDT exhibits hypoxic tumor therapeutic inefficiency,requirement of heavy atom doping and limited therapeutic depth,which restrict the further applications.Photoinduced electron transfer（PET）is a classic molecular excited-stated regulation mechanism,which can improve the therapeutic efficiency by quenching radiative transition.Among the most organic molecule dyes,cyanine dyes are an ideal photosensitizer parent frame due to their adjustable excitation wavelengths,large molar extinction coefficients and good biocompabibility.This dissertation aims to design and develop cyanine photosensitive dyes based on PET to solve the above-mentioned issues in PDT.The specific researches are shown as follows:To overcome the low PDT efficiency under hypoxia,the photosensitive dye Icy-NBF with oxygen content induced regulation of excited state deactivation pathways was developed,in which,iodine modified heptamethine cyanine dye（Cy7）was utilized as photosensitizer frame.By modifying hypoxia-triggered PET group at the meso position of the parent frame,smart phototherapy mode with PDT in normoxia and photothermal therapy（PTT）in hypoxia is realized.Compare with clinical used near infared（NIR）photosensitizer,Icy-NBF exhibits 2-folds photon ultilization improvement and can cause efficient photo-destruction towards cancer cells under either normoxia or hypoxia,resulting in the total inhibition and even partial elimination of solid tumors.To circumvent the applicable drawbacks of heavy atom doping such as shortened triplet lifetime and weak stability,a series of heavy-atom-free photosensitive dyes were developed based on the parent structure of pentamethine cyanine dye（Cy5）.By modifying different electron donors with large steric hindrance effect at the meso position of the parent structure,the intersystem crossing（ISC）efficiency is enhanced with the help of PET and the excited-state lifetime is elongated,in the meanwhile,the photophysical properties advantages of Cy5 are retained.ANOMe-Cy5 exhibits 4.48-folds higher ¹O₂ generation and 9.80-folds longer triplet lifetime compared with conventional Cy5,and shows better photosensitization effect than heavy-atom modified dye under hypoxic conditions.Finally,ANOMe-Cy5 realized in vivo breast orthotopic tumor photoablation and inhibition of cancer lung metastasis.To further elongate the treatment depth of the heavy-atom-free photosensitive dye system,one-photon upconversion evaluation was tested on the prepared Cy5-based dye.The study discovered that the rotatable anthracene group in XAN-Cy5 is able to simultaneously increase the hot band absorption（HBA）efficiency and enhance ISC via PET,by which,XAN-Cy5exhibits more than 2-folds improvement of ¹O₂ generation even compared with meso-heavy-atom modified dye and results in photoablation of deep-seated tumor.Moreover,both the photostability and signal-to-noise ratio of cyanines are improved by upconverison excitation,which is much longer that the molecular maximum absorption wavelength.The modification strategy is also successfully applied in in Cy5 analogs which verifies the general instruction of the improvement of HBA efficiency to the final enhancement of upconversion photosensitization.