Study On The Treatment Of Hepatocellular Carcinoma And Recurrence By Magnetic Mesoporous Nanoparticles With Doxorubicin And Berberine

Hepatocarcinoma is one of the malignant tumors that seriously endanger the health of people.Although there has been considerable progress in the treatment of liver cancer,it has not been able to effectively change the rising tendency of its incidence and mortality.Recurrence and metastasis after treatment are the leading causes of death in liver cancer patients.Therefore,the mechanism of recurrence and metastasis of hepatocellular carcinoma is the key to improve the therapeutic efficiency of liver cancer and improve the survival rate of patients.Recent studies have shown that the activated caspase-3 proteins in tumor cells after radiotherapy can play an important role in stimulating tumor repopulation through caspase-3-iPLA₂-AA-PGE₂,or"phoenix nirvana"signaling pathway.In addition,we also confirmed that berberine can inhibit the repopulation of hepatocellular carcinoma cells.Therefore,we proposed a combined therapy strategy of doxorubicin and berberine in the treatment of hepatocellular carcinoma to inhibit the recurrence of hepatocellular carcinoma.However,due to the difference of the solubility of doxorubicin and berberine in water,traditional methods of administration cannot achieve this strategy ideally.It is currently urgent to develop an administration system with better tumor targeting ability,biocompatible and intracellular sequential drug release.In the previous work of our lab,the Janus magnetic-mesoporous silica carrier?Fe₃O₄-MSNs?has been successfully developed,which avoids the disadvantages of the magnetic susceptibility of the magnetic-mesoporous with spherical shell structure.At the same time,the magnetic head and the mesoporous rod do not interfere with each other in structure and function.Janus Fe₃O₄-MSNs have the characteristics of large drug loading capacity,good biocompatibility,high endocytosis efficiency,and pH responsive drug release in tumor cells which is the ideal carrier for the co-deliver of doxorubicin and berberine.Objective:The purpose of this study is to verify the combination of doxorubicin and berberine by blocking the"phoenix nirvana"signaling pathway to treat liver cancer and to inhibit its recurrence.In this paper,we describe the synthesis scheme of magnetic-mesoporous silica nanoparticles for hepatocellular carcinoma?HCC?.This system has realized the strategy of treating hepatocellular carcinoma with high efficiency and low toxicity while inhibiting tumor recurrence.Methods and results:1)In this study,a recurrence model of doxorubicin induced hepatocellular carcinoma was successfully established in vitro and in vivo,and the results confirmed that berberine could inhibit the reproliferation of HepG2 cells in human liver cancer induced by doxorubicin.It was confirmed that berberine combined with doxorubicin could inhibit the recurrence of liver cancer after chemotherapy by blocking the caspase 3-iPLA₂-COX-2"phoenix nirvana"signaling pathway2)We prepared a kind of multifunctional nanoparticles:Janus-magnetic mesoporous silica nanoparticles?Fe₃O₄-MSNs?,with the surface modified by hyaluronic acid?HA?and nano fluorescent probe quantum dots?QD?,and chemotherapy drug doxorubicin and berberine,Fe₃O₄-MSN/Dox+Ber@HA-QD.The in vitro experiments showed that the nanoparticles could selectively enter HepG2cells through the CD44 receptor mediated endocytosis pathway and release Dox and Ber rapidly,which had better cytotoxic effects at low concentrations?P<0.05?.The in vivo results also suggested that he nanoparticles have a significantly lower recurrence of the hepatocellular carcinoma induced by Dox and significantly reduced the toxic and side effect of doxorubicin while having a better antitumor effect than other groups.In addition,the nanoparticles can also achieve MRI and fluorescence imaging of the tumor site,providing the possibility of drug delivery and therapeutic effects.Conclusion:To sum up,this paper confirmed that berberine in combination with doxorubicin can block Caspase 3-iPLA₂-COX-2"phoenix nirvana"signaling pathways,to inhibit the repopulation of hepatocellular carcinoma after chemotherapy.We prepared the multifunctional Janus type nanoparticles?Fe₃O₄-MSN/Dox+Ber@HA-QD?with high efficiency and low toxicity in the treatment of liver cancer and inhibit tumor recurrence.