Preparation And Synergistic Treatment Mechanisms Of Porphyrin Derivatives Based Microcapsule For Phototherapy And Chemotherapy In Tumor

Photodynamic Therapy(PDT)is a new method for cancer treatment,and has become the fourth treatment on cancer besides surgery,radiotherapy,chemical therapy.Photosensitizer which dominates the function of PDT is the hardest bottleneck to breakthrough in development of PDT.In recent years,scholars have been trying to combine PDT with various treatment programs,in which the combined chemotherapy received much attention.Currently,both of simple single and combined medications inevitably display side effects on normal cells.In order to reduce the side effects of drugs,drug delivery system with specific functions is considered as a hotspot and a promising way for tumor therapy.However,owing to limits of carriers materials,drug carriers have some drawbacks,including low affinity,small drug package quantity and drug leakage in process of delivery.With respect to these problems,we developed a novel photodynamic drug carrier microcapsules loaded with chemotherapeutic drugs for synergistic treatment for cancer therapy.In this study,a novel polyene porphyrin photosensitizer was synthesized.The porphyrin is linked to dimethylaminoethyl methacrylate(DM)through the addition polymerization of double bonds,and doxorubicin hydrochloride(DOX)is enclosed in the microcapsule cavity.Thus,a drug carrier having dual therapeutic effect of phototherapy and chemotherapy was prepared.To the best of our knowledge,such drug carriers with high drug encapsulation efficiency and synergistic therapy function have not been reported.After optimized preparation,the microcapsules were utilized for tumour cell therapy,and the results will provide some basic research reference on cancer therapy.The main works are listed as follows:(1)Meso-5,10,15,20-tetrakis(4-hydroxyphenyl)-21 H,23H-porphine(H2THPP)was acquired after a reaction of p-hydroxy benzaldehyde and pyrrole.Subsequently,H2 THPP was modified with methacryloyl chloride to afford meso-5,10,15,20-tetrakis[4-(methacryloyloxy)phenyl]-21 H,23H-porphyrin(TMa BPP)via nucleophilic substitution reaction.(2)Microcapsules loaded with DOX(DOX@poly(TMaBPP-DM))and microcapsules(poly(TMaBPP-DM))were both prepared via interfacial polymerization between TMaBPP and dimethylaminoethyl methacrylate(DM).Under optimized conditions,microcapsules with high drug loading rate,entrapment efficiency and uniform size were synthesized.FT-IR spectrum of poly(TMa BPP-DM)suggested the successful polymerization between TMaBPP and DM.Optical microscope and scanning electron microscope images of DOX@poly(TMaBPP-DM)showed that microcapsules loaded with DOX were synthesized successfully.Excellent drug loading rate and encapsulation efficiency of microcapsules were confirmed by fluorescence spectrophotometer measurement.The contact angle measurement results showed the good hydrophilicity of microcapsules.Particle size analyzer characterization demonstrated the controllability of microcapsule size ranging from nanoscale to microscale.(3)Release behavior of DOX from DOX@poly(TMaBPP-DM)microcapsule in oil and water had been evaluated respectively.In oil,effects of temperature and illumination dose on release of DOX from microcapsule to outside oil solution were studied.Meanwhile,effects of temperature,pH and illumination dose on release of DOX from microcapsule surface to ambient water solution were studied.The results suggested that release behavior of DOX would be affected by temperature,pH and illumination dose,which provided the effective preservation of microcapsules loaded with drug and their utilization on tumour cell experiments.(4)Cell viabilities of human immortalized epidermal cells HaCaT and skin melanoma cells A375 were investigated after incubation of cells and DOX,poly(TMaBPP-DM),DOX@poly(TMaBPP-DM)and DOX-poly(TMaBPP-DM)with different concentrationsand various illumination doses.The results suggested that poly(TMaBPP-DM)showed high phototoxicity with illumination even under low concentration,indicating an excellent phototherapy effect of microcapsule.And poly(TMaBPP-DM)displayed relatively lower toxicity on HaCaT,while higher toxicity on A375 without illumination.In addition,compared to that of poly(TMaBPP-DM)-DOX,DOX@poly(TMaBPP-DM)showed lower toxicity on HaCaT,while higher toxicity on A375,especially with illumination.Furthermore,results obtained by analysis of Jin's formula suggested that DOX@poly(TMaBPP-DM)display excellent synergy therapy efficiency induced by PDT and chemotherapy of as-prepared drug delivery system.