Synthesis And Activity Evaluation Of Photosensitizers Based On Chlorin Skeleton

Photodynamic therapy?PDT?is a new and clinically approved method for the treatment of cancer with low invasive-characteristic.Compared with the traditional methods for the treatment of malignant tumors,photodynamic therapy has the advantages of strong selectivity,repeatable treatment,low treatment cost and less systemic side effects.However,PDT is still faced with great challenges such as limited tissue penetration,low tolerance of hypoxic tissue and poor targeting of photosensitizers.As one of the key factors of photodynamic therapy,development of photosensitizer with potent photo-cytotoxicity,low dark cytotoxicity,high specificity and fast clearance from body has always been a research hotspot in the field of photodynamic therapy for tumors.Chlorin e6,one of the degradation products of chlorophyll a,has been widely concerned as photosensitizer due to its special spectral properties,high singlet oxygen yield,and multiple modifiable sites in skeleton.5-aminolevulinic acid?5-ALA?is an endogenous precursor for the production of photosensitive protoporphyrin IX and involves in the heme cycle in cells.The exogenous 5-ALA has been widely used as the second generation of photosensitizer for the treatment of actinic keratosis and other diseases in dermatology.However,due to the instability and high hydrophilicity of 5-ALA,its transmembrane capacity is greatly limited and its bioavailability is decreased.Therefore,in this thesis,six novel photosensitizers based on the skeleton of chlorin e6 and5-aminolevulinic acid were obtained by covalent coupling.The photophysical properties,photochemical stability,singlet oxygen yields,cell uptake rate and in vitro PDT effects of these6 compounds were investigated.All these compounds retained the spectral properties of chlorin e6.The compound bearing methyl ester group have higher photochemical stability,cell uptake rate and has low dark toxicity and superior phototoxicity.agaist Hela cells than the compounds with free carboxyl groups.Among these compounds,2c,3a and 4a exhibited much more significant PDT effects than chlorin e6 with submicromolar concentration of IC₅₀.The phototoxicity of 2c was the highest,102 times compared with chlorin e6.The findings suggest that the introduction of 5-ALA into chlorin e6 can markedly enhance the PDT effects and lead to a new type of photosensitizers with potential therapeutic application.