Study on anti-hepatocellular carcinoma efficacy of glycyrrhetinic acid-modified curcumin-loaded cationic liposomes
Objective To investigate the liver targeting of glycyrrhizic acid-modified curcumin-loaded cationic liposomes(GAMCLC)and its anticancer effects.Methods Prepared glycyrrhetinic acid(GA)ligands-GA and octadecylamine salt(SGO)and detected them using infrared spectroscopy and mass spectrometry,and further used SGO to prepare GAMCLC,and observed the morphology of liposomes under transmission electron microscopy,and measured the particle size and potential of liposomes using Nano ZS90 nanoparticle size analyzer.Using a live imaging system to observe the fluorescence distribution in GAMCLC mice.Wistar rats were randomly divided into a control group,a model group,a doxorubicin(positive drug,2 mg·kg-1)group,a curcumin(20 mg·kg-1)group,and a GAMCLCL low and high dose(2,4 mg·kg-1)group.Except for the control group,a Walker-256 cell seeding method was used to prepare a liver orthotopic transplantation tumor model.The rats were administered once a day for 7 consecutive days,and set up a 14 day group of GAMCLCL(4 mg·kg-1)for administration.Weighed the tumor mass,calculated the liver coefficient and spleen coefficient.The levels of red blood cells(RBC),white blood cells(WBC),platelets(PLT),alanine aminotransferase(ALT),and creatinine(CRE)were measured using a fully automated biochemical analyzer,and lactate dehydrogenase(LDH)levels were detected using a reagent kit method.ELISA method was used for detecting serum tumor necrosis factor-α(TNF-α)and the level of interleukin-6(IL-6).Western blotting was used to detect the expression levels of vascular endothelial growth factor(VEGF),cleaved Caspase-3,Bcl-2,p53,p-PI3K,and p-AKT proteins in tumor tissues.Results The results of infrared spectroscopy and mass spectrometry could verify that the reaction between GA and octadecylamine generated SGO.GAMCLCL had a spherical appearance with a particle size of(194±0.25)nm,a polymer dispersibility index(PDI)of 0.21±0.02,and a potential of(31.9±0.31)mV.GAMCLCL appeared as a yellow transparent solution within two months,with no precipitation.GAMCLCL did not exhibit any aggregation or precipitation when mixed with serum.Live imaging experiments showed that fluorescence was mainly concentrated in the liver at various time points after administration.The liver fluorescence was strong at 10,30,and 60 min,significantly weakened at 120 min,and basically disappeared at 240 min.Compared with model group,the tumor mass of rats in each treatment group was significantly reduced(P＜0.05,0.01).The liver coefficient significantly decreased in each treatment group(P＜0.05,0.01),while the spleen coefficient significantly decreased in the free curcumin group and GAMCLCL 4 mg·kg-1(7,14 d)group(P＜0.01).The RBC and PLT counts were significantly increased(P＜0.01)and WBC counts were significantly decreased(P＜0.05,0.01)in the groups of doxorubicin and GAMCLCL 4 mg·kg-1(7,14 d).ALT and CRE of rats in each treatment group were significantly reduced(P＜0.05,0.01).Except for the free curcumin group,LDH in each treatment group was significantly reduced(P＜0.05,0.01).IL-6 and TNF-α in each administration group significantly decreased(P＜0.01,0.05).The protein expression of VEGF,Bcl-2,AKT,and p-PI3K in each treatment group was significantly downregulated(P＜0.05,0.01),while the protein expression of cleaved Caspase-3 and p53 was significantly upregulated(P＜0.05,0.01).The anti-tumor effects of GAMCLCL(4 mg·kg-1)administered for 7 d and 14 d were similar,significantly stronger than free curcumin.Conclusion GAMCLCL significantly enhanced the liver-targeting and anti-hepatocellular carcinoma effects of curcumin,and was beneficial to the progression-free survival of tumor-bearing rats.
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