Construction And Application Of Porphyrin-based Nanodrug Delivery Systems

To overcome the problems of lack of tumor selectivity and poor water solubility of small-molecule photosensitizers,the small-molecule photosensitizers and carriers were combined into nanodrug delivery systems by physical encapsulation or chemical bonding to improve the photodynamic therapy effect.At the same time,due to the heterogeneity of tumors and other reasons,photodynamic therapy alone could not fully achieve satisfactory therapeutic effects.Therefore,according to the mechanisms of different treatment methods,photodynamic therapy was used in combination with other treatment methods to further improve theanti-tumor effects.In this paper,poly?L-glutamic acid??PLG?,which was degradable and has good biocompatibility,was used as the carrier to construct porphyrin nanoparticles that enhance photodynamic therapy effect.Andon this basis,combined with vascular targeting therapy to construct nanodrug delivery systems for combined treatment of tumor tissues.The details are as follow:?1?The biodegradable PLG was used as the carrier to prepare two kinds of porphyrin nanoparticles with photosensitizers 5-?4-aminophenyl?-10,15,20-triphenylporphyrin?TPP-NH₂?by physical encapsulation and covalent combination,improving the defects of tumor selectivity and poor water solubility of small molecule photosensitizer.Among them,the porphyrin nanoparticles prepared by covalently binding TPP-NH₂ can well interrupt the ?-? stacking between TPP-NH₂ and avoid the aggregation of photosensitizer to suppress the quenching effect.However,due to the rigid structure of TPP-NH₂ and its hydrophobic ?-? stacking effect,the physical blending can easily cause TPP-NH₂ aggregating and quenching,which reduces its PDT effect.Cell experiments showed that TPP-NH₂ had stronger fluorescence intensity and reactive oxygen generation capacity in PT incubated cells,and had better inhibitory effect on tumor cells.?2?In order to significantly enhance the tumor treatment effect and improve the disadvantages of monotherapy,on the basis of the previous system,PLG was chemically bonded to the photosensitizer TPP-NH₂ and the vascular disrupting agents Combretastatin A4?CA4?to prepare nanoparticles PT?PLG-graft-TPP-NH₂?and PC?PLG-graft-CA4?,which were used to construct nanodrug delivery systems for synergetic photodynamic therapy and vascular targeting therapy.The solubility of the drugs and the endocytosis of the nanoparticles were enhanced in the designed nanodrug delivery systems.After the nanoparticles are internalized by the tumor cells,PT and PC would release TPP-NH₂ and CA4,respectively.The released TPP-NH₂ killed tumor cells near the blood vessels by producing cytotoxic singlet oxygen under laser irradiation,and the released CA4 mainly caused necrosis in the central area of the tumor by blocking blood vessels.In vivo and in vitro experiments showed that the nanodrug delivery systems exhibited more satisfactory antiproliferative effect compared to monotherapy.