Preparation and evaluation of dual-targeting pH-sensitive baicalin/curcumin co-loaded liposomes
Objective To optimize the formulation process of dual-targeted pH-sensitive baicalin/curcumin co-loaded liposomes(GA/FA-pH-Lip@Bai/Cur)and evaluate their properties.Methods GA/FA-pH-Lip@Bai/Cur was prepared using a thin film dispersion ultrasonication method.The evaluation criteria included encapsulation efficiency,similarity factor(f2)of release curves in different pH media,particle size,and polydispersity index(PDI).The optimal formulation process was determined through single-factor testing and Box-Behnken design-response surface methodology to evaluate the liposomes'morphology,particle size,and in vitro release profiles at different pH levels.The biocompatibility of GA/FA-pH-Lip@Bai/Cur was assessed through a hemolysis test.The in vitro inhibitory effect of baicalin,curcumin,baicalin/curcumin(mass ratio 5∶1)mixed solution,GA/FA-pH-Lip@Bai/Cur on liver cancer cells(HepG2)was examined using the CCK-8 assay.The liver targeting of GA/FA-pH-Lip@Bai/Cur in vivo was investigated through a mouse tissue distribution experiment.Subsequently,pharmacological experiments were conducted to study the antitumor efficacy of GA/FA-pH-Lip@Bai/Cur on H22 tumor-bearing mice and its impact on histopathological changes of tumor tissue after HE staining,serum TNF-α and IL-6 levels.Results The optimal preparation method for GA/FA-pH-Lip@Bai/Cur was as follows:The ratio of baicalin to curcumin was 5∶1,the ratio of cholesteryl succinate(CHEMS)to phospholipids was 2∶10,the ratio of DSPE-PEG 2000 to phospholipids was 4∶100,the ratio of DSPE-PEG-GA to phospholipids was 2∶100,the hydration volume was 10 mL,the ratio of phospholipids to drugs was 7.95:1,and the ratio of phospholipids to cholesterol was 6.53∶1,and the ultrasonic crushing time was 69 s.The optimized GA/FA-pH-Lip@Bai/Cur exhibited an encapsulation efficiency of 90.90％for baicalin and 90.97％for curcumin,with an average particle size of 82.5 nm and sustained-release behavior.The IC50 of baicalin for HepG2 cells was approximately five times that of curcumin,and the IC50 of GA/FA-pH-Lip@Bai/Cur was lower than that of the mixed solution.The in vivo pharmacodynamic evaluation results show that the tumor inhibition rate of GA/FA-pH-Lip@Bai/Cur was comparable to that of 5-fluorouracil(5-FU).The number of necrotic cells in the treated group decreased,the arrangement of tumor cells becomes loose,and the cells showed varying degrees of shrinkage,and the levels of TNF-α and IL-6 in the serum were significantly lower than those in the model group(P＜0.01).Conclusion The GA/FA-pH-Lip@Bai/Cur prepared had good safety and high liver targeting,and has good inhibitory effects on liver tumors.
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