一种氟化纳米给药系统通过抑制阿霉素外排逆转MCF-7/ADR细胞耐药性的研究

A study on reversing multidrug resistance of MCF-7/ADR cells by inhibiting doxorubicin efflux with a fluorinated nanomedicine delivery system

目的通过合成氟化纳米材料完成对阿霉素(doxorubicin,dox)的高效负载,并实现纳米药物对抗肿瘤耐药的机制研究。方法评估不同氟化程度(PF4和PF8)的纳米药物(nano dox)的理化性能,筛选出更为优良的氟化nano dox;通过细胞毒性、细胞摄取、凋亡以及对抗外排泵P-糖蛋白(P-glycoprotein,P-gp)的研究,考察nano dox对抗肿瘤多药耐药以及体外抗肿瘤活性研究。结果通过考察各种理化指标,PF8相对于PF4显示出更优良的负载dox性能;通过细胞毒性实验证明,nano dox的IC 50值只有游离dox IC 50值的1/40,显示出nano dox在对抗耐药性方面优良的体外活性;细胞摄取和凋亡研究说明nano dox可以有效提高耐药MCF-7/ADR细胞对dox的摄取并能成功地进入细胞核内,最终导致凋亡诱导的抗癌活性;P-gp的药物外排研究说明nano dox可以有效绕过P-gp外排泵,达到增加耐药细胞对药物的摄取同时减少外排量的双重作用。结论通过氟化nano dox的设计可以有效绕过P-gp对药物的外排作用,增加药物在耐药肿瘤细胞内的摄取,减少其外排,从而达到有效的对抗肿瘤多药耐药效果。

Aim To achieve efficient loading of doxorubicin(doxorubicin,dox)by synthesizing fluorinated nanomaterials,and to study the mechanism of nanomedicine against multidrug resistance in tumors.Methods The physicochemical properties of nano dox(nano-doxorubicin)at different degrees of fluorination(PF4 and PF8)were evaluated through various physi-cochemical parameters,and nano dox formulations were screened out with superior fluorination.The mechanism of nano dox in overcoming multidrug resistance in tumors was investigated and in vitro anti-tumor activity was studied through research on cytotoxicity,cellular uptake,apoptosis,and resistance against the P-glycoprotein(P-glycoprotein,P-gp)efflux pump.Results By examining various physicochemical indicators,PF8 exhibited superior nano performance in loading doxorubicin compared to PF4.Cytotoxicity experiments demonstrated that the IC 50 value of nano dox was only 1/40 of free dox,indicating excellent in vitro activity of nano dox in overcoming resistance and inhibiting cell proliferation.Cell uptake and apoptosis studies indicated that nano dox could effectively enhance the uptake of doxorubicin in MCF-7/ADR cells and successfully enter the cell nucleus,ultimately leading to apoptosis-induced anticancer activity.Studies on drug efflux mediated by P-glycoprotein indicated that nano dox could rapidly enter MCF-7/ADR cells through an efficient cellular uptake pathway,effectively bypassing the P-glycoprotein efflux pump.This dual action resulted in increased drug uptake within resistant cells and a reduction in efflux,demonstrating the potential of nano doxorubicin to overcome drug resistance.Conclusions The design of fluorinated nano dox effectively circumvents the efflux of drug molecules by P-glycoprotein,enhancing drug uptake within resistant tumor cells and reducing efflux.This results in an effective strategy in combating multidrug resistance in tumors.