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文献报道他莫昔芬能够增强载药脂质体的细胞摄取,其具体机制仍有待研究,有研究者推测此现象是由他莫昔芬抑制P-糖蛋白对药物的外排作用而造成的。本研究为进一步阐明该作用的机理,制备了PEG修饰、共包载他莫昔芬的P-糖蛋白底物阿霉素脂质体及非底物香豆素-6脂质体,研究了不同P-糖蛋白表达水平的细胞对载药脂质体的摄取情况,及包载他莫昔芬后脂质体与脂膜的相互作用。结果表明,共包载他莫昔芬能显著提高所选三种细胞对阿霉素脂质体的摄取,且摄取增加水平与P-糖蛋白表达水平相关。同时,共包载他莫昔芬能显著增加非P-糖蛋白底物香豆素-6脂质体的摄取,对阿霉素脂质体在P-糖蛋白表达阴性的Hela细胞中的摄取也有显著促进作用。表面等离子共振技术证明他莫昔芬脂质体与模型生物膜的亲和力强于不载药的空白脂质体,等温滴定量热技术证明游离他莫昔芬与模型生物膜有明显亲和作用。综上,他莫昔芬能够增强脂质体和生物膜的亲和力,通过抑制P-糖蛋白对药物的外排、提高脂质体和细胞膜的结合两方面的共同作用提高细胞对脂质体的摄取。
It is reported in the literature that tamoxifen can enhance the cellular uptake of drug-loaded liposomes. The specific mechanism remains to be studied. Some researchers speculate that this phenomenon is caused by the inhibition of the efflux of P-glycoprotein by tamoxifen . In order to further elucidate the mechanism of this action, this study prepared a PEG modified, co-coated with tamoxifen substrate of doxorubicin Doxorubicin liposomes and non-substrate coumarin-6 liposomes, studied The uptake of liposomes by different P-glycoprotein-expressing cells and the interaction between liposome and lipid membrane after entrapment of Tamoxifen. The results showed that co-inclusion of tamoxifen significantly increased uptake of doxorubicin liposomes in the three selected cells, and the uptake level correlated with the expression of P-glycoprotein. At the same time, tamoxifen co-inclusion significantly increased uptake of non-P-glycoprotein coumarin-6 liposomes, uptake of doxorubicin liposomes in P-glycoprotein negative Hela cells Also have a significant role in promoting. Surface plasmon resonance demonstrated that tamoxifen liposomes had better affinity with model biofilm than blank liposomes. Isothermal titration calorimetry proved that free tamoxifen had obvious affinity with model biofilm. Taken together, tamoxifen enhances the affinity of liposomes and biofilms and enhances the effect of liposomes on the liposomes by inhibiting the efflux of P-glycoprotein and enhancing the combination of liposomes and cell membranes Ingest.