Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG)

被引：37
作者：
Chandran, Thripthy [1 ]
Katragadda, Usha [1 ]
Teng, Quincy [2 ]
Tan, Chalet [1 ]
机构：
[1] Mercer Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Atlanta, GA 30341 USA
[2] US EPA, Natl Exposure Res Lab, Athens, GA 30605 USA
来源：
INTERNATIONAL JOURNAL OF PHARMACEUTICS | 2010年 / 392卷 / 1-2期
关键词：
Polymeric micelles; PEG-DSPE; TPGS; 17-AAG; Drug release; PHASE-II TRIAL; TANESPIMYCIN; 17-AAG; TISSUE DISTRIBUTION; MIXED MICELLES; BREAST-CANCER; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; PACLITAXEL; PHARMACOKINETICS; GELDANAMYCIN; COMBINATION;
D O I：
10.1016/j.ijpharm.2010.03.056
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
17-Allyamino-17-demethoxygeldanamycin (17-AAG) is a potent anticancer agent currently undergoing phases I and II clinical trials. However, the clinical development of 17-AAG has been hindered by its poor aqueous solubility and hepatotoxicity. This study aimed to devise novel micellar nanocarriers for 17-AAG that improve its solubility and retain the incorporated drug for a prolonged period of time. We have found that 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)2000]/D-alpha-tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles (at a 1:2 molar ratio) can deliver 17-AAG at clinically relevant doses. By modulating the concentrations of micelle-forming copolymers, the burst release of 17-AAG from PEG-DSPE/TPGS mixed micelles was substantially reduced with a release half-life up to about 8 h. Our H-1 NMR spectroscopy results revealed that the incorporation of TPGS into PEG-DSPE micelles restricted internal molecular motions of copolymers in both the corona and core regions of the micelles, leading to the delayed drug release. Cytotoxicity of 17-AAG formulated in PEG-DSPE/TPGS mixed micelles against human ovarian cancer SKOV-3 cells was comparable to that of free 17-MG. 17-AAG-loaded PEG-DSPE/TPGS mixed micelles may offer a promising alternative to the current 17-MG formulations for the treatment of solid tumors. (C) 2010 Elsevier B.V. All rights reserved.
引用
收藏
页码：170 / 177
页数：8
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