Project supported by grants from the National Natural Science Foundation of China (No 30600769 and 30672407) and the Key Science and Technology Foundation of Guangdong Province, China (No 2005B10401042).
FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo1
Article first published online: 24 MAY 2007
Acta Pharmacologica Sinica
Volume 28, Issue 6, pages 913–920, June 2007
How to Cite
DENG, W.-j., YANG, X.-q., LIANG, Y.-j., CHEN, L.-m., YAN, Y.-y., SHUAI, X.-t. and FU, L.-w. (2007), FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo. Acta Pharmacologica Sinica, 28: 913–920. doi: 10.1111/j.1745-7254.2007.00565.x
- Issue published online: 24 MAY 2007
- Article first published online: 24 MAY 2007
- Received 2006-10-25; Accepted 2006-12-29
- micellar nanoparticle;
- multidrug resistance;
Aim: 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.