Study Of Sulfated Glycolipid Micelles For Cancer Therapy

Cancer is the main reason that seriously threatens human health.Previous studies showed that cancer cells can overexpress heparan sulfate proteoglycan(HSPG),which binds with signaling factors by the interactions between heparan sulfate(HS)chain and proteins,to promote tumor proliferation,metastasis,and angiogenesis.Therefore,the strategies,which interferes the biological function of HSPG and induces apoptosis might be a new approach for cancer therapy.In this study,two derivatives with different sulfated structures were synthesized from N-acetylglucosamine(GlcNAc).Then,the derivatives were modified with hydrophobic stearic acid to obtain amphiphilic glycolipids,which were assembled to form micelles.Finally,HepG2 cells were used as a model to investigate the inhibition effects of glycolipid micelles on cancer cell and tumor growth in vitro and in vivo.Further information are listed below:First,the classification,structural characteristics,and biological functions of HSPG were reviewed and summarized.Also,the treatment strategies of HSPG were analyzed.Second,GlcNAc derivatives(G1,G2,and G3)and amphiphilic glycolipids(SGL1,SGL2,and SGL3)were synthesized.The chemical structure was verified.The particle size of the self-assembly micelles(SGLM1,SGLM2,and SGLM3)were observed between 50-100 nm by transmission electron microscopy,while the hydrated diameters measured by dynamic light scattering were 100.1,110.2,and 118.6 nm.Among then,the zeta potentials of SGLM2 and SGLM3 were-8.48 and-17.67 mV.The hemolysis rates of the derivatives and glycolipids were less than 3%,showing good blood compatibility.Third,the cytotoxicity and anti-tumor effect of the derivatives and glycolipids were investigated.The results showed that the survival rate of normal cells(COS7,L02,Beas-2b)with the samples were above 60% at a concentration of 400 mg/L,showing good compatibility.However,the samples inhibited tumor cells(B16,HepG2,A549,MGC80-3)growth.SGLM2 and SGLM3 inhibited the growth of HepG2 and A549 cells at the concentration of 400 mg/L,because they efficiently internalized and accumulated in the mitochondria,and finally induced cell apoptosis.The apoptosis-inducing ability of HepG2 cells was SGL3 > SGL2,showing a concentration-dependent manner.The late apoptosis rate of SGL3-induced cells was 61.64%,and the overall apoptosis rate was 71.71%.In addition,SGL3 could block HepG2 cells at the S + G2/M phase.At a concentration of 300 mg/L,the G2/M phase was 28.9%,which is 8.11% higher than the control group.Finally,the solid tumor model was constructed to evaluate the anti-tumor activity of the samples in vivo.The results showed that the SGLM3 group significantly inhibited the growth of tumor tissue,with the inhibition rate reached 92.63%.The cell morphology and growth of the tumor tissue were observed by H&E and TUNEL staining,respectively.The cells in the SGLM3 group were severely apoptotic,with an apoptosis rate of 23.42%.In addition,the body weight and organ weight of mice were not affected,while showing no obvious liver and kidney toxicity,and good bio-safety.Based on the understanding of the mechanism of HSPG in the pathological process of cancer,starting from the structure of HSPG,this study prepared sulfated glycolipid micelles with anti-tumor activity to provide a pro-strategy for cancer treatment.