Synthesis And Evaluation Of Targeted Nanomicelle Delivery System With Rhein As The Hydrophobic End And Its Synergistic Therapy Effect On Tumor

Objective: To design and prepare a targeted nanomicelle drug delivery system with rhein as the hydrophobic end to increase the water solubility of rhein,improve the drug loading of rhein micelles and tumor targeting,and to load anti-tumor drugs with different mechanisms to play a synergistic anti-tumor effect.Methods: Amphiphilic macromolecule folic acid-polyethylene glycol-rhein(FA-PEG-RH)was synthesized by acylation reaction.Thin layer chromatography was impolyed to monitor the synthesis of micellar drug delivery system.Column chromatography was used to separate the synthesis system,and infrared spectrum together with nuclear magnetic spectroscopy were used to characterize the product.Laser dynamic scattering instrument was applied to anlyze the particle size of micelles,zeta potential and polydispersity index.The encapsulation efficiency and drug loading were evaluated by application of dialysis and high performance liquid chromatography.The ability of micelles uptaken by tumor cells was investigated with fluorescent dye-loaded FA-PEG-RH nanomicelles.The MTT cell test was conducted to investigate the inhibitory effect of empty nanomicelles on tumor cell growth.The synergistic therapy effect in vitro was separately verified with zinc phthalocyanine and nanomicelles containing zinc phthalocyanine(Zn Pc)incubated with tumor cells.Hela tumor cells-bearing nude mice were adopted to evaluate in vivo anti-tumor effect.Results: The structure of the nano-amphiphilic macromolecule synthesized by acylation was basically consistent with the design.The micelle prepared by the organic solvent evaporation method had better physical and chemical properties,and the particle size was 215.69 ± 22.24 nm,zeta potential was-22.3 mv.The drug loading and encapsulation efficiency of FA-PEG-RH micelles loaded with rhein were 8.13% ± 0.92% and 82.03% ± 9.1%,respectively.In vitro fluorescence imaging showed that FA-PEG-RH micelles can pass through the cell membrane and be uptaken by tumor cells within 4hours.The MTT test of Hela cells showed that blank FA-PEG-RH micelles had an inhibitory effect on tumor cells.The MTT test of M109 cells and in vivo anti-tumor test showed that under 660 nm,200 mw laser irradiation,Zn Pc loaded with FA-PEG-RH nanomicelles demonstrated stronger anti-tumor effect than others.Conclusion: The folic acid-polyethylene glycol 2000-rhein conjugate was used to prepare nanomicelles with organic solvent evaporation method.The micelles had small particle size,high drug loading,and were relatively stable.Blank FA-PEG-RH nanomicelles had the inhibitory effect of tumor cell growth.Nanomicelles loaded with phthalocyanine zinc and other chemicals with different anti-tumor mechanisms can play synergistic anti-tumor effect.