RGD脂肪醇与17-AAG脂质体的制备及抗肿瘤活性研究

doi:10.3969/j.issn.1006-7795.2015.02.004

首都医科大学学报 ›› 2015, Vol. 36 ›› Issue (2): 172-177.doi: 10.3969/j.issn.1006-7795.2015.02.004

RGD脂肪醇与17-AAG脂质体的制备及抗肿瘤活性研究

李雪梅¹, 王玉记², 吴建辉², 崔纯莹¹

1. 首都医科大学化学生物学与药学院药剂学系, 北京 100069;
2. 首都医科大学化学生物学与药学院药物化学系, 北京 100069

收稿日期:2014-12-08 出版日期:2015-04-21 发布日期:2015-04-16
通讯作者: 崔纯莹 E-mail:cyc@ccmu.edu.cn
基金资助:
"十二五"重大新药创制科技重大专项(2011ZX09302-007-01)。

Preparation and anti-tumor activity of a novel liposome-loaded drug

Lu Xuemei¹, Wang Yuji², Wu Jianhui², Cui Chunying¹

1. Department of Pharmaceutics, School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China;
2. Department of Medicinal Chemistry, School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China

Received:2014-12-08 Online:2015-04-21 Published:2015-04-16
Supported by:
This study was supported by Significant New Drugs Creation "Five-year" Plan Special Science and Technology Major(2011ZX09302-007-01).

摘要/Abstract

摘要： 目的制备一种新的精氨酸-甘氨酸-天冬氨酸-苯丙氨酸-脂肪醇(Arg-Gly-Asp-Phe-fatty alcohol,RGDFOC₁₂)与17-丙烯氨基-17-去甲氧基格尔德霉素(17-allylamino-17-demethoxygeldanamycin,17-AAG)的脂质体(RGDFOC₁₂ liposomes-loaded 17-AAG,RLAs)。方法采用薄膜分散-探头超声法制备;采用激光纳米粒度仪、透射电镜和扫描电镜测定粒径,Zeta电位和外观形态;采用动态透析法测定药物释放;采用四甲基偶氮唑盐[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT]考察其对5种人肿瘤细胞株增生的抑制作用;通过瘤质量、存活数、体质量、脏器指数比评价其在小鼠体内抗肿瘤效果。结果制备得到的RLAs的粒径为(130.6±0.6)nm,Zeta电位为(-28.37±1.67)mV,外观形态为球形,包封率为80%以上。RLAs在pH 5.4环境的累积释放百分数大于在pH 7.4环境的累积释放百分数。RLAs在血浆中可稳定存在,12 h累积释放百分数为(15.85±0.71)%。RLAs对5种肿瘤细胞有抑制增生作用。RLAs对接种S180腹水瘤的ICR小鼠有抑制肿瘤生长作用。结论本研究制备了一种新的RLAs,制备方法简单、包封率高,具有较好的抗肿瘤活性。

关键词: 抗肿瘤, 17-丙烯胺基-17-去甲氧基格尔德霉素(17-AAG), 精氨酸-甘氨酸-天冬氨酸-苯丙氨酸-脂肪醇(RGDFOC₁₂)

Abstract: Objective To prepare an Arg-Gly-Asp-Phe-fatty alcohol(RGDFOC₁₂) liposomes-loaded 17-allylamino-17-demethoxygeldanamycin(17-AAG). Methods RGDFOC₁₂ liposomes-loaded 17-AAG(RLAs) was prepared by film dispersion method and evaluated by particle size analysis, Zeta potential, encapsulation efficiency, the release in vitro, plasma stability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay and the anti-tumor activity in vivo. Results The RLAs was stable colloidal dispersion system in spherical shape of (130.6±0.6)nm in diameter and the Zeta potential was (-28.37±1.67)mV. The release of RLAs in vitro showed that the released percentage of RLAs in pH 5.4 is more than that in pH 7.4. The MTT assay proved that RLAs inhibited the proliferation of cancer cells. The anti-tumor assay showed that RLAs inhibited tumor growth and reduced the toxicity. Conclusion The RLAs were prepared by film dispersion method. RLAs showed anti-tumor activity in vivo and good potential in cancer therapy.

Key words: anti-tumor, 17-allylamino-17-demethoxygeldanamycin(17-AAG), Arg-Gly-Asp-Phe-fatty alcohol(RGDFOC₁₂)

中图分类号:

R965.1

李雪梅, 王玉记, 吴建辉, 崔纯莹. RGD脂肪醇与17-AAG脂质体的制备及抗肿瘤活性研究[J]. 首都医科大学学报, 2015, 36(2): 172-177.

Lu Xuemei, Wang Yuji, Wu Jianhui, Cui Chunying. Preparation and anti-tumor activity of a novel liposome-loaded drug[J]. Journal of Capital Medical University, 2015, 36(2): 172-177.

参考文献

[1] Öyüksel H, Mohanty P S, Rubinstein I. VIP-grafted sterically stabilized phospholipid nanomicellar 17-allylamino-17-demethoxy geldanamycin:a novel targeted nanomedicine for breast cancer[J]. Int J Pharm, 2009,365:157-161.
[2] Chandran T, Katragadda U, Teng Q, et al. Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxy-geldanamycin(17-AAG)[J]. Int J Pharm, 2010,392:170-177.
[3] 孙维彤,张娜.托氟叮脂质体的研究[J].中国药学杂志,2007,42(6):445-449.
[4] Chiosis G, Vilenchik M, Kim J, et al. Hsp90:The vulnerable chaperone[J]. Drug Discov Today, 2004,9(20):881-888.
[5] Scheibel T, Buchner J. The Hsp90 complex-a super-chaperone machine as a novel drug target[J]. Biochem Pharmcol, 1998,56(6):675-682.
[6] Holzbeierlein J M, Windsperger A, Vielhauer G. Hsp90:A drug target?[J]. Curr Oncol Rep, 2010,12(2):95-101.
[7] Isaacs J S, Xu W, Neckers L.Heat shock protein 90 as a molecular target for cancer therapeutics[J]. Cancer Cell, 2003,3(3):213-217.
[8] Konstantinopoulos P A, Papavassiliou A G. 17-AAG:mechanisms of antitumour activity[J]. Expert Opin Investig Drugs, 2005,14(12):1471-1474.
[9] Saxena V, Naguib Y, Hussain M. Folate receptor targeted 17-allylamino-17-demethoxygeldanamycin(17-AAG) loaded polymeric nanoparticles for breast cancer[J]. Colloids Surf B Biointerfaces, 2012,94:274-280.
[10] Meyer P N, Roychowdhury S, Kini A R, et al. HSP90 inhibitor 17AAG causes apoptosis in ATRA-resistant acute promyelocytic leukemia cells[J]. Leuke Res, 2008,32(1):143-149.
[11] Williams C R, Tabios R, Linehan W M, et al. Intratumor injection of the Hsp90 inhibitor 17AAG decreases tumor growth and induces apoptosis in a prostate cancer xenograft model[J]. J Urol, 2007,178(4 pt 1):1528-1532.
[12] Chung Y L, Troy H, Ronen U, et al. Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino,17-demethoxygeldanamycin(17-AAG) in human colon cancer models[J]. J Natl Cancer Inst, 2003,95(21):1624-1633.
[13] 肖丽君,赵恩宏,赵爽,等.17-AAG对MCF-7细胞增殖的抑制作用及对STAT3和VEGF表达的影响[J].中国医科大学学报,2013,42(1):65-68.

RGD脂肪醇与17-AAG脂质体的制备及抗肿瘤活性研究

Preparation and anti-tumor activity of a novel liposome-loaded drug

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