PDT Anti-tumor System Based On Disulfide Bonds

Malignant tumor is one of the major diseases that threaten human health.Photodynamic therapy(PDT)is an important treatment for cancer.The principle is that the light stimulates the photosensitizer enriched in the tumor site,and generates reactive oxygen species(ROS)to kill the tumor cells.Therefore,PDT is a tumor treatment method based on oxidative damage.Compared with clinical surgical resection,chemotherapy and radiation therapy,PDT has the advantages of less damage to healthy tissue,low toxic and side effects,less postoperative complications and economical convenience.However,in clinical advancement,PDT tumor treatment was limited by many factors,such as insufficient photosensitizer self-targeting(limited distribution and retention of tumor sites)and high concentrations of reduced glutathione(consuming ROS produced by PDT)in tumor cells,severely restrict PDT activity.In order to solve the above problems,the following research was conducted in this paper:1.The photosensitizer itself is insufficiently targeted,resulting in limited distribution and retention of photosensitizing drugs at the tumor site,which limits the effective treatment of PDT.Intratumoral administration and para-tumor administration are two classical ways of elevating tumor tissue for drug uptake.Compared with intratumoral administration,para-tumor administration can not only effectively increase the uptake of photosensitizing drugs by tumor cells,but also avoid the risk of tumor metastasis caused by intratumoral administration.Based on this,a synthetic DMSO-triggered disulfide-coupled hyaluronic acid hydrogel(HA-ss-HA)was designed as a drug carrier for para-tumor administration.Compared to other complex synthetic hydrogels,HA-ss-HA hydrogel uses a more easily synthesized thiolated hyaluronic acid as a raw material,which is triggered by a mild oxidizing dimethyl sulfoxide(DMSO)solvent.DMSO can be used not only as a trigger for gelation reactions,but also as a solvent for drugs.Therefore,the above hydrogel can achieve efficient loading of the drug.In vitro and in vivo experiments show that HA-ss-HA hydrogel can effectively release the photosensitive drug zinc phthalocyanine(ZnPc)under physiological conditions,and HA-ss-HA hydrogel can be used after one treatment cycle(two weeks).Degradation in the body.Animal model experimental data showed that ZnPc can only inhibit tumor growth for 7 days after thyroid administration,and ZnPc@HA-ss-HA can effectively inhibit tumor growth within two weeks.Based on this research,HA-ss-HA hydrogel was developed as a para-tumor carrier for chemotherapeutic drugs(DOX),hyperthermia(ICG)and nano-thermographic materials(Pd nanosheets).In vivo studies have shown that after intratumoral administration,various drugs loaded in the hydrogel can be slowly and slowly released into the tumor tissue,killing the tumor cells and effectively inhibiting tumor growth.2.High concentrations of reduced glutathione in tumor cells consume large amounts of ROS produced by PDT,severely reducing PDT activity.The introduction of functional groups with GSH damage on photosensitizing drugs can effectively reduce intracellular GSH content and enhance PDT antitumor activity.Based on this,a novel ZnPc photosensitive drug(ZnPc-DTP)containing disulfide at the end was designed and synthesized and nanosized.Intracellular GSH can react with ZnPc-DTP to form GSSG without reducing activity and convert ZnPc-DTP into ZnPc-SH with high PDT activity.In vivo fluorescence imaging experiments in small animals can be observed that ZnPc-DTP can be effectively enriched in tumor sites.After the PDT treatment by ZnPc-DTP,the concentration of GSH in the cells decreased by 70.83%,however,the concentration of GSH in the cells decreased by 30.84%after PDT treatment by ZnPc-SH.In vitro anti-tumor experiments showed that ZnPc-DTP can enhance the PDT effect by depleting GSH in tumor cells and effectively inhibit tumor growth.