伊马替尼胶束的制备与体外克服肿瘤耐药性的研究

Preparation of Imatinib Micelles and Research on in Vitro Overcoming Tumor Drug Resistance

目的伊马替尼(imatinib,IMN)包埋于托可索仑(tocofersolan,TPGS)胶束中,以提高其水溶性,并对其理化性质进行表征,及与人源耐药细胞株MCF-7/ADR的作用效果。通过TPGS胶束运输IMN进入细胞,可克服肿瘤细胞的多药耐药性,提高抗肿瘤效果,为进一步体内药效研究提供基础。方法采用薄膜分散法制备IMN-TPGS胶束,对其粒径、电位、形态、载药量和包封率及体外释放行为进行表征,考察该胶束对MCF-7/ADR细胞的抗肿瘤效果。结果IMN-TPGS胶束平均粒径为(22.69±2.39)nm,表面呈电中性,外观圆整,载药量为(1.55±0.06)%,包封率为(63.49±2.42)%;具有较高的耐稀释性,血清稳定性和冻干-复溶稳定性;在体外释放72 h后,累积释放度近100%,释放速率缓慢;IMN-TPGS胶束对MCF-7/ADR的IC_(50)为12.27μmol·L^(-1),细胞毒性大,细胞内药物含量高,可诱导近半数细胞凋亡。结论IMN-TPGS胶束粒径均一,分散性良好,稳定性高,具有较强抗稀释性,有利于体液长循环,对耐药细胞株有明显的抗肿瘤效果,在一定程度上可以克服其多药耐药性。

OBJECTIVE To embed imatinib(IMN)into micelles based on tocofersolan(TPGS)matrix,charecterize the physical and chemical properties of IMN-TPGS micelles and improve the anti-tumor effect.METHODS The thin film dispersion method was used to prepare IMN-TPGS micelles,and their particle size distribution,surface potential,morphology,drug loading,encapsulation efficiency and in vitro release behavior were characterized.The in vitro anti-tumor effect of IMN-TPGS micelles was investigated on MCF-7/ADR cells.RESULTS The average particle size of IMN-TPGS micelles was(22.69±2.39)nm,the drug loading was(1.55±0.06)%,and the encapsulation efficiency was(63.49±2.42)%.IMN-TPGS micelles with neutral surface showed a nearly sphere appearance.There was no significant change in diameter and drug loading after dilution times.IMN-TPGS micelles could be stable in the serum solution for 24 h.There was no significant difference in its particle size and encapsulation efficiency before and after freeze-drying.The in vitro cumulative release of IMN from TPGS micelles was close to 100%after 72 hours with a slow rate.The IC_(50) of the IMN-loaded TPGS micelles was 12.27μmol·L^(-1) consistent with its significant cellular uptake in MCF-7/ADR cells.CONCLUSION IMN-TPGS micelles with uniform particle size,good dispersibility and high stability,showed strong anti-dilution properties,which were conducive to the long circulation in body fluids.IMN-TPGS micelles exhibit obvious anti-tumor effects on drug-resistant cell lines,which could overcome multidrug resistance to a certain extent.