FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo
FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo
复制标题
负载 FG020326 的 PEG 和 PDLLA 纳米粒子改善了体外和体内逆转多药耐药性的药效学
DOI：
10.1111/j.1745-7254.2007.00565.x
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发表时间：
2007-06-01
影响因子：
8.2
通讯作者：
Fu, Li-wu
中科院分区：
文献类型：
--
作者：
Deng, Wen-jing;Yang, Xiao-qiang;Fu, Li-wu
摘要目的：FG 020326是一种新型的咪唑衍生物，在体内外均具有很强的多药耐药（MDR）调节作用。然而，FG 020326是不溶的。PEDLLA-FG 020326是由聚（乙二醇）-嵌段-聚（D，L-乳酸）（PEG：PDLLA，PEDLLA）的二嵌段共聚物形成的载有FG 020326的纳米颗粒，可溶解FG 020326。本研究旨在评价PEDLLA-FG 020326在体内外逆转MDR的药效学。采用荧光分光光度法检测阿霉素（Dox）的细胞内积聚和外排。流式细胞术检测细胞内罗丹明123（Rh 123）的积累，检测P-糖蛋白的功能。结果：PEDLLA-FG 020326和FG 020326对KBv 200细胞长春新碱（VCR）耐药的逆转活性分别为56.4倍和35.9倍，对阿霉素（Dox）耐药的逆转活性分别为14.98倍和7.64倍。PEDLLA-FG 020326的作用强于FG 020326，导致KBv 200细胞中Dox和Rh 123积累增加，细胞内Dox排出减少。重要的是，PEDLLA-FG 020326表现出更强大的活性比FG 020326在增强VCR对KBv 200细胞裸鼠移植瘤的作用，但并没有出现更多的toxic.Conclusion：FG 020326的药效学改善，通过将其纳入胶束纳米粒与PEG-嵌段-PDLLA共聚物形成。
AbstractAim:FG020326, a novel imidazole derivative, is a potent multidrug-resistance (MDR) modulator in vitro and in vivo. However, FG020326 is insoluble. PEDLLA-FG020326 is a FG020326-loaded nanoparticle formed with diblock copolymers of poly (ethylene glycol)-block-poly (D,L-lactic acid) (PEG:PDLLA, PEDLLA) that can solubilize FG020326. This work was intended to evaluate the pharmacodynamics of PEDLLA-FG020326 on reversing MDR in vitro and in vivo.Methods:Cytotoxicity was determined by tetrazolium assay. The intracellular accumulation and efflux of doxorubicin (Dox) were detected by fluorescence spectrophotometry. The function of P-glycoprotein was examined by Rhodamine 123 (Rh123) accumulation detected by flow cytometry. The KBv200 cell xenograft model was established to investigate the effect of PEDLLA-FG020326 on reversing MDR in vivo.Results:PEDLLA-FG020326 and FG020326 exhibited 56.4- and 35.9-fold activity in reversing KBv200 cells to vincristine (VCR) resistance, respectively and 14.98-and 7.64-fold to Dox resistance, respectively. PEDLLA-FG020326 was much stronger than FG020326, resulting in the increase of Dox and Rh123 accumulation and the decrease of intracellular Dox extrusion in KBv200 cells. Importantly, PEDLLA-FG020326 exhibited more powerful activity than FG020326 in enhancing the effect of VCR against KBv200 cell xenografts in nude mice, but did not appear more toxic.Conclusion:The pharmacodynamics of FG020326 was improved by incorporating it into a micellar nanoparticle formed with PEG-block-PDLLA copolymers.