Multifunctional Ferritin-based Nanoparticles For Co-drug Delivery To Circumyent Cancer Resistance

gastric cancer was the fourth most frequently diagnosed cancer,he cause of death due to gastric cancer occupy the third.There are 951,600 new cases and 723,100 deaths worldwide.Although the prevalence of gastric cancer is high in the world,but in East Asia is the highest.Depending on the state of the tumor,surgery,chemotherapy and radiotherapy may be used to treat gastric cancer.Chemotherapy is the first choice for patients with metastatic gastric cancer,but only by surgery is very limited.In addition to the side effects of chemotherapy drugs on the body,another important issue is the increased tolerance of cancer cells to drugs,that is,drug resistance(MDR).And once the emergence of drug resistance,even to find alternative chemotherapy drugs or increase the use of drugs,can not fundamentally solve the problem.Thus,there is an urgent need for new ways to tackle cancer resistance problems.The main mechanism of cancer drug resistance are the high expression of P-gp and heavy chain ferritin(HFn),Co-delivery of anticancer chemotherapeutics and siRNAs targeting MDR genes in the same nanoparticle can drastically enhance therapeutic efficacy.The expression of P-glycoprotein on the cell membrane decreased by siRNA,Reduced the efflux of chemotherapy drugs,the drugs stay in the cytoplasm do a therapeutic effect.At the same time,nanoparticles which encapsulated chemotherapy drugs play a role on endogenous heavy chain ferritin,improve the therapeutic effect of the drug.Because high expression expression of endogenous heavy chain ferritin contribute to protect reactive oxygen species produced by chemotherapy drugs from elimination.In this study,we used the natural protein cage heavy chain ferritin(Fn)as a vector,The N-terminal of exterior surfaces subunit was modified the cell-penetrating,a cationic peptide peptide rich in arginine genetically.,forming the fusion protein TAT-Fn.Then the P-gp siRNA was binding with TAT-Fn though electrostatic interaction,and chemotherapeutic drug doxicin wasEncapsulated in the ferritin,The P-gp siRNA/TAT-Fn-Dox nanocomplex was used co-therapy for multi-drug resistant cancer cells(SCG 7901/VCR).The results show that TAT-Fn nanoparticles are very stable,can effectively load with P-gp siRNA and Doxorubicin(Dox),not only reverses the multidrug resistance of the tumor,while avoiding the systemic toxicity of chemotherapy alone.In addition,we first found that exogenous ferritin-loaded with drugs,not only will not increase the expression of endogenous heavy chain ferritin,but reduced the expression of heavy chain ferritin,on the other hand,reversal of the Tumor multidrug resistance,enhanced the effect of chemotherapy.