Research on Preparation and Photodynamic Therapy Anti-cancer Biological Activity of Chlorophyll Photosensitizers

Author:Tan Guang Hui

Supervisor:qu feng yu

Database:Doctor

Degree Year:2019

Download:37

Pages:111

Size:8212K

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Cancers are severe human diseases second only the cardiovascular diseases.Conventional therapy against cancers has some shortcomings such as the serious side effects for chemotherapeutic drugs and trauma for surgery.Therefore,developing novel anticancer drugs has always been a goal for researchers.Photo Dynamic therapy(PDT)is a novel method for cancertreatment since the 1970s,and has been a regular therapy in clinic by far.PDT is based on thatexcited photosensitizer(PS)interacts with molecular triplet oxygen to produce radicals and reactive oxygen species,therebyeliciting cell death.The key of PDT is PS,most of which are tetrapyrrolic compounds with several shortcomings such as relative short absorption wavelength,weak tissue penetrating ability,easy aggregation,poor target towards tumors,leading to unsatisfactory therapeutic efficacy.The main degradation products of chlorophyll are chlorin compounds,whose structural core is 18π-aromaticconjugation system with many active synthetic sites,providing good conditions for structural modifications.In this paper,we have prepared several novel near-infrared active PSs with excellent biocompatibility and targetability,and studied the in vitro activities.We have prepared 3-acetyl-3-devinyl-131-dicyanomethylenepyropheo phorbide-a(ADCPPa)and C-31,131-bisphenylhydrazonemodified methyl pyropheophorbide-a(BPHM)through peripheral modification of methyl pyropheophorbide-a,and established the in vitro PDT experimental model based on HeLa cells,SKOV-3 cells and MCF-7 cells.The longest absorption wavelength of ADCPPa and BPHMwere 713 nm and 700 nm respectively,red-shifting 53 nm and 40 nm compared with methyl pyropheophorbide-a,and consequently improving the tissue penetration depth.Moreover,the in vitro activities of ADCPPa and BPHM were also studied,which suggested that the formation of singlet oxygen(Type II mechanism)after PDT treatment played a major role,comparing with the formation of superoxide anion and radicals.The PSs could have important regulating effects on expression of CDK2 and Survivin,consequently leading to apoptosis and cell death.we have also studied the preparative methods and in vitro antitumor activities of magneticfluorescence nanoparticles.We selected pyropheophoribde-a as the PS,and prepared a magnetic iron oxide modified pyropheophoribde-a fluorescence nanoparticles,Fe3O4@SiO2@APTES@PPa(FSAP)(FSAP)with nuique fluorescence characteristic and targetability,through continuous covalently chemical modification on the surface of Fe3O4 nanoparticles.FSAP showed remarkable photototoxicity after irradiation,good biocompatibility and could be uptaken successfully and quickly by the tumor cells.All in all,our obtained ADCPPa,BPHM,FSAP showed excellent antitumor PDT activity,and have great potential application for PDT in clinic practice.In addition,a novel photosensitizer graphene loaded with 13-chlorophyllic acid-a p-bromophenylhydrazone(G-BPMPPa)was prepared and its structure was characterized.The photodynamic antitumor activity of PDT in vitro was also studied.The results showed that G-BPMPPa had good dispersibility in water and could enter cells faster than BPMPPa,PDT had significant effect.