| Liver cancer is the fifth most common cancer worldwide ane the third most common cause of cancer deaths.It has very high incidence and lack effective treatment in China at present.Increasing evidence suggests that liver cancer is caused by cancer stem cells and the cure of liver cancer requires eradication of liver cancer stem cells.Liver cancer stem cells(LCSC)play importment roles in the relapse of liver cancer because they are resistant to the standard chemotherapy and the residual cancer stem cells are able to proliferate.Sulforaphane(SFN)is a kind of isothiocyanate enriched in the plant family of Brassicaceae and present in high concentration in broccoli.SFN can inhibit cancer stem cells by reducing phase?cytochrome P450 enzymes,inducing phase ? metabolic enzymes,and inducing cell cycle arrest and apoptosis.Sorafenib tosylate(ST),a novel multikinase inhibitor,has shown promising antitumor activity.STcan inhibit vascular endothelial growth factor(VEGF)receptor-2 and VEGF receptor-3 expressed by endothelial cells and CD133+ circulating hematopoietic progenitor cells [3] and platelet-derived growth factor receptor-?,FLT3,Ret,and c-Kit expressed by vasculature associated cells and tumor cells.Aming to both kill liver cancer cells and liver cancer stem cells,we developed sulforaphane loaded mesoporous silica nanoparticle(MSN)supported liposomes(SFN/MSN/LIPs)and sorafenib tosylate loaded MSN supported liposomes(ST/MSN/LIPs).First,we established the determination methods of sulforaphane and sorafenib tosylate by HPLC.The results showed that in the range of 2.52?161.50?g?mL-1,concentration have a good correlation with the sample peak area(R2=0.9993).The linear regression equation was A=40,238,415C+57,864.The results also showed that in the range of 1.96?62.69?g?mL-1,ST concentration had a good correlation with the sample peak area(R2=0.999).The linear regression equation was A=88885C+45916.The specificity,linearity,precision,recovery and stability are all required,so it can be used for the determination of the sulforaphane or sorafenib tosylate contents.Mesoporous silica nanoparticles were prepared successfully with templating method.By tuning the pH of media to acidic,and then departing the conjugating nanoparticles by ultrasonicater or microfluidizer,the stability of the system was improved.Modified with AEPTMS,mesoporous silica nanoparticles had good dispersibility in neutral dispersing agent.Mesoporous structure,dispersity,surface appearence,particle size and zeta potential of MSN were investigated by transmission electron microscopy(TEM),scanning electron microscopy(SEM)and laser Nano Zetasizer.Surface area and cumulative pore volume were measured by Nitrogen adsorption-desorption.The particles have well-formed spherical shapes evidenced by TEM and SEM images.Particles have fully accessible three-dimensional pore networks.The release rates were lower in PBS(pH 7.4)at 37°C,than in PBS(pH 5.0)at 37°C,which is good for cytoxicity.HepG2 microspheres(HepG2-MS)were isolated from HepG2 cell lines with characteristics of stem cells which are cultured in non serum medium.Then the cytotoxicity of SFN was investigated in HepG2 cells and HepG2-MS.The coeffect of SFN and ST to HepG2 were investigated.The result showed that at the ratio of 1:5(SFN to ST),synergistic effect was exhibited in HepG2 cell lines and HepG2 microsphere.From experiments of endocytosis and cytotoxicity,the MSN/LIPs exhibited targeting effets.Using Hep G2 tumor-bearing nude mice,we evaluated the therapeutic efficacy of SFN/MSN/LIPs and ST/MSN/LIPs.The results exhibited that blank MSN/LIPs had good compatibility,and SFN or ST bearing MSN/LIPs showed strong efficacy to liver cancer.In summary,the designed drug delivery system of SFN and ST showed high loading capacity,high safety profile,and can simultaneously play killing effect on liver cancer cells and liver cancer stem cells with the best activity.This provides a prospective clinical choice for the therapy of liver cancer. |
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