Study On The Photosensitive Anti-tumor Activity Of Autophagy Or Iron Death Synergistic

Malignant tumors pose a serious threat to human health,so it is of great significance to find effective treatment methods.Photodynamic therapy(PDT)has the advantages of low side effects,drug resistance and low systemic toxicity,and has a broad application prospect in the field of tumor treatment.Multi-mechanism synergistic treatment can achieve better anticancer effect and has broad prospects in biomedical research and clinical practice of tumor treatment.In this paper,autophagy promoting drugs and ferroptosis-inducing drugs were combined with photosensitive drugs phtihalocyanine(ZnPc),respectively,to achieve efficient tumor treatment through multi-mechanisms synergistic effect.The specific research content and results are as follows:1.Research on synergistic tumor treatment between "autophagy activation" and "photodynamic therapy"Vascular dysplasia in tumor tissues leads to a lack of nutrients,which can easily activate autophagy in tumor cells.Relative studies have shown that autophagy can play an opposite role in promoting cell survival or death in tumor therapy under different conditions.Reactive oxygen species(ROS)produced during PDT treatment can induce autophagy.Whether promoting autophagy or inhibiting autophagy will affect PDT activity in PDT process has not been reported yet.To clarify this problem,the effects of autophagy promoters(Rapa)and autophagy inhibitors(chloroquine,CQ and 6-amino-3-methypurine,3-MA)on the anti-tumor activity of PDT were first studied in this paper.It was found that Rapa,an autophagy promoter,significantly increased PDT anti-tumor activity at very low drug concentrations(autophagy promoter or autophagy inhibitor alone had no tumor cell killing effect),while autophagy inhibitor CQ and 3-MA had no such effect.Based on this,polyamide dendritic molecules(RSV)containing thioacetal groups which could be triggered by ROS were synthesized,and composite nano-drugs Rapa@RSV@Pc were formed by self-assembling loaded with Rapa and ZnPc.When injected intravenously into tumor-bearing mice,nanomaterials deliver Rapa and ZnPc to tumor sites.Selective illumination on tumor sites can stimulate ZnPc to produce ROS,trigger thioacetal fracture to destroy micelles,release Rapa,and realize autophagy promotion and PDT synergistic tumor treatment.Experiments in vitro showed that the combination of "autophagy activation" and "photodynamic therapy" can achieve ideal tumor therapeutic effect.Compared with PDT alone(24.8%tumor kill rate),the combination therapy significantly improved tumor cell killing efficiency(76.8%tumor kill rate).Experiments in vivo showed that Rapa@RSV@Pc could effectively accumulate in tumor tissues and significantly improve tumor inhibition effect(tumor size decreased by 20.7%in single PDT treatment and 54.8%in combination therapy).2.Research on synergistic cancer treatment between "ferroptosis promotion" and"photodynamic therapy"Ferroptosis is a new form of programmed cell necrosis,which leads to the production of reactive oxygen species and lipid peroxidation with the accumulation of large amounts of iron ions.PDT tumor therapy is also based on the oxidative damage of biological molecules produced by reactive oxygen species.Therefore,we hypothesized that the synergistic effect of ferroptosis and PDT could enhance oxidative damage of tumor cells and enhance anti-tumor activity.In vivo studies have shown that Erastin significantly increases PDT anti-tumor activity at very low drug concentrations(Erastin alone has no cancer-killing effect).Based on this,Era@RSV@Pc is composed of Erastin,a nano-micelle co-loaded ferroptosis inducer formed by self-assembly of polyamide dendritic molecules,and ZnPc,a photosensitive agent,to ensure synchronous delivery of the two drugs in vivo,synchronous enrichment of tumor tissues and synchronous activity.The results of studies in vivo indicate that Era@RSV@Pc may be enriched in tumor tissues by enhancing permeability and retaining(EPR)effect of nanoparticles after it is injected into tumor-bearing mice through tail vein.After selective illumination of tumor tissues,ZnPc produces ROS to trigger the PDT process and induce thioacetal fracture in micellar structure,releasing Erastin.Finally,"ferroptosis promotion" and "photodynamic therapy" combined with efficient tumor treatment were achieved(in vitro experiment,the inhibition rate of single PDT treatment was 41.4%,and the inhibition rate of combined therapy was 77.3%.In vivo experiments,tumor size was reduced by 13.5%with PDT alone and 29.2%with combination therapy.)...