叶酸与TPGS修饰的负载多西他赛的DSPE-PEG胶束的制备和抗耐药肿瘤研究

doi:10.5246/jcps.2015.07.054

中国药学(英文版) ›› 2015, Vol. 24 ›› Issue (7): 419-426.DOI: 10.5246/jcps.2015.07.054

• 【研究论文】 • 下一篇

叶酸与TPGS修饰的负载多西他赛的DSPE-PEG胶束的制备和抗耐药肿瘤研究

王爱婷^2#, 佟淑文^2,4#, 胡新^2*, 齐宪荣^1,2,3*

1. 北京大学医学部分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 北京大学医学部药学院药剂学系, 北京 100191
3. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
4. 北京泰德制药股份有限公司, 北京 100176

收稿日期:2015-04-11 修回日期:2015-04-17 出版日期:2015-07-28 发布日期:2015-05-08
通讯作者: Tel.: 86-10-82801708, 86-10-82801584
基金资助:
National Natural Science Foundation of China (Grant No. 81273454 and 81473156), Beijing National Science Foundation (Grant No. 7132113), National Key Basic Research Program (Grant No. 2013CB932501), and Doctoral Foundation of the Ministry of Education (Grant No. 20130001110055).

Preparation and anti-MDR tumors study of folate and TPGS dual-modified DSPE-PEG micelles loaded with docetaxel

Aiting Wang^2#, Shuwen Tong^2,4#, Xin Hu^2*, Xianrong Qi^1,2,3*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Peking University Health Science Center, Beijing 100191, China
2. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
4. Tide Pharmaceutical Co., Ltd., Beijing 100176, China

Received:2015-04-11 Revised:2015-04-17 Online:2015-07-28 Published:2015-05-08
Contact: Tel.: 86-10-82801708, 86-10-82801584
Supported by:
National Natural Science Foundation of China (Grant No. 81273454 and 81473156), Beijing National Science Foundation (Grant No. 7132113), National Key Basic Research Program (Grant No. 2013CB932501), and Doctoral Foundation of the Ministry of Education (Grant No. 20130001110055).

摘要/Abstract

摘要：

由P-糖蛋白引起的多药耐药是肿瘤治疗失败的主要原因之一。本研究制备了以DSPE-PEG₂₀₀₀和TPGS₁₀₀₀为脂材、以叶酸为主动靶向配体的负载多西他赛的胶束, 用于克服肿瘤多药耐药并降低毒副作用。本研究评价了不同TPGS₁₀₀₀比例对胶束性质和抗耐药肿瘤能力的影响。制备的胶束粒径在13–26 nm,包封率均大于85%。TPGS₁₀₀₀比例的增加可提高耐药肿瘤细胞对胶束的摄取, 也可提高胶束对耐药肿瘤细胞的毒性。此外, 对于叶酸受体阳性表达的耐药肿瘤细胞, 叶酸修饰的胶束有更强的抗肿瘤效果。研究表明, 叶酸与TPGS₁₀₀₀共同修饰的胶束对叶酸受体过表达的耐药性肿瘤有更好的治疗效果。

关键词: 胶束, 多药耐药, 制备, DSPE-PEG, TPGS, 叶酸

Abstract:

Multidrug resistance (MDR) operated by P-glycoprotein (P-gp) is one of the major causes in the treatment failure of cancers. In this work,docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene-glycol)₂₀₀₀ (DSPE-PEG₂₀₀₀),D-α-Tocopherylpolyethylene glycol 1000 succinate (TPGS₁₀₀₀) and DSPE-PEG₂₀₀₀-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG₂₀₀₀ and TPGS₁₀₀₀ ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS₁₀₀₀ amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells.The study provides a method for overcoming MDR in cancer therapy.

Key words: Micelles, Multidrug resistance, Preparation, DSPE-PEG, TPGS, Folate

中图分类号:

R944

Supporting:

王爱婷, 佟淑文, 胡新, 齐宪荣. 叶酸与TPGS修饰的负载多西他赛的DSPE-PEG胶束的制备和抗耐药肿瘤研究[J]. 中国药学(英文版), 2015, 24(7): 419-426.

Aiting Wang, Shuwen Tong, Xin Hu, Xianrong Qi. Preparation and anti-MDR tumors study of folate and TPGS dual-modified DSPE-PEG micelles loaded with docetaxel[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(7): 419-426.

参考文献

[1] Ganguly, A.; Banerjee, K.; Chakraborty, P.; Das, S.; Sarkar, A.; Hazra, A.; Banerjee, M.; Maity, A. Chatterjee, M.; Mondal, N.B.; Choudhuri, S.K. Biomed. Pharmacother. 2011, 65, 387-394.

[2] Batrakova, E.V.; Li, S.; Brynskikh, A.M.; Sharma, A.K.; Li, Y.L.; Boska, M.; Gong, N.; Mosley, R.L.; Alakhov, V.Y.; Gendelman, H.E.; Kabanov, A.V. J. Control. Release. 2010, 143, 290-301.

[3] Krishna, R.; Mayer, L.D. Eur. J. Pharm. Sci. 2000, 11, 265-283.

[4] Li-Blatter, X.C.; Nervi, P.; Seelig, A. BBA-Biomembranes. 2009, 1788, 2335-2344.

[5] Nervi, P.; Li-Blatter, X.C.; Aanismaa, P.; Seelig, A. BBA-Biomembranes. 2010, 1798, 515-525.

[6] Sikic, B.I.; Fisher, G.A.; Lum, B.L.; Halsey, J.; Beketic-Oreskovic, L.; Chen, G. Cancer Chemother. Pharm. 1997, 40, S13-S19.

[7] Coley, H.M. Multi-Drug Resistance in Cancer, Methods in Molecular Biology. 2010, 596, 341-358.

[8] Jakate, A.S.; Einhaus, C.M.; DeAnglis, A.P.; Retzinger, G.S.; Desai, P.B. Cancer Res. 2003, 63, 7314-7320.

[9] Bissery, M.C. Eur. J. Cancer. 1995, 31A, S1-S6.

[10] Izquierdo, M.A.; Garcia, M.; Ponton, J.L.; Martinez, M.; Valenti, V.; Navarro, M.; Gil, M.; Gardenal, F.; Mesia, R.; Perez, X.; Salazar, R.; Germa-Lluch, J.R. Eur. J. Cancer. 2006, 42, 1789-1796.

[11] Elsabahy, M.; Perron, M.E.; Bertrand, N.; Yu, G.; Leroux, J.C. Biomacromolecules. 2007, 8, 2250-2257.

[12] Liu, J.B.; Zahedi, P.; Zeng, F.Q.; Allen, C. J. Pharm. Sci. 2008, 97, 3274-3290.

[13] Cesur, H.; Rubinstein, I.; Pai, A.; Onyuksel, H. Nanomed-Nanotechnol. 2009, 5, 178-183.

[14] Tong, S.W.; Xiang, B.; Dong, D.W.; Qi, X.R. Int. J. Pharm. 2012, 434, 413-419.

[15] Cao, N.; Feng, S.S. Biomaterials. 2008, 29, 3856-3865.

[16] Collnot, E.M.; Baldes, C.; Wempe, M.F.; Hyatt, J.; Navarro, L.; Edgar, K.J.; Schaefer, U.F.; Lehr, C.M. J. Control. Release. 2006, 111, 35-40.

[17] Park, E.K.; Kim, S.Y.; Lee, S.B.; Lee, Y.M. J. Control. Release. 2005, 109, 158-168.

[18] Han, X.; Liu, J.; Liu, M.; Xie, C.; Zhan, C.Y.; Gu, B.; Liu, Y. Int. J. Pharm. 2009, 372, 125-131.

[19] Wu, J.; Liu, Q.; Lee, R.J. Int. J. Pharm. 2006, 316, 148-153.

[20] Gao, W.; Xiang, B.; Meng, T.T.; Liu, F.; Qi, X.R. Biomaterials. 2013, 34, 4137-4149.

[21] Photos, P.J.; Bacakova, L.; Discher, B.; Bates, F.S.; Discher, D.E. J. Control. Release. 2003, 90, 323-334.

[22] Wang, A.T.; Liang, D.S.; Liu, Y.J.; Qi, X.R. Biomaterials. 2015, 53, 160-172.

[23] Liu, B.R.; Yang, M.; Li, R.T.; Ding, Y.T.; Qian, X.P.; Yu, L.X.; Jiang, X.Q. Eur. J. Pharm. Biopharm. 2008, 69, 527-534.

[24] Meaden, E.R.; Hoggard, P.G.; Khoo, S.H.; Back, D.J. J. Immunol. Methods. 2002, 262, 159-165.

[25] Fiskus, W.; Rao, R.; Fernandez, P.; Herger, B.; Yang, Y.H.; Chen, J.G.; Kolhe, R.; Mandawat, A.; Wang, Y.C.; Joshi, R.; Eaton, K.; Lee, P.; Atadja, P.; Peiper, S.; Bhalla, K. Blood. 2008, 112, 2896-2905.

[26] Mu, C.F.; Balakrishnan, P.; Cui, F.D.; Yin, Y.M.; Lee, Y.B.; Choi, H.G.; Yong, C.S.; Chung, S.J.; Shim, C.K.; Kim, D.D. Biomaterials. 2010, 31, 2371-2379.

[27] Wang, X.; Wang, Y.G.; Chen, X.M.; Wang, J.C.; Zhang, X.; Zhang, Q. J. Control. Release. 2009, 139, 56-62.

[28] Bae, Y.H.; Park, K. J. Control. Release. 2011, 153, 198-205.

[29] Gill, K.K.; Kaddoumi, A.; Nazzal, S. Eur. J. Pharm. Sci. 2012, 46, 64-71.

[30] Sawant, R.R.; Sawant, R.M.; Torchilin, V.P. Eur. J. Pharm. Biopharm. 2008, 70, 51-57.

[31] Mu, L.; Elbayoumi, T.A.; Torchilin, V.P. Int. J. Pharm. 2005, 306, 142-149.

[32] Wang, Y.Z.; Fan, W.; Dai, X.; Katragadda, U.; Mckinley, D.; Teng, Q.; Tan, C. Mol. Pharm. 2014, 11, 1140-1150.

[33] Minko, T.; Batrakova, E.V.; Li, S.; Li, Y.L.; Pakunlu, R.I.; Alakhov, V.Y.; Kabanov, A.V. J. Control. Release. 2005, 105, 269-278.

[34] Barz, M.; Arminan, A.; Canal, F.; Wolf, F.; Koynov, K.; Frey, H.; Zentel, R.; Vicent, M.J. J. Control. Release. 2012, 163, 63-74.

[35] Rege, B.D.; Kao, J.P.Y.; Polli, J.E. Eur. J. Pharm. Sci. 2002, 16, 237-246.

[36] Collnot, E.M.; Baldes, C.; Wempe, M.F.; Kappl, R.; Huttermann, J.; Hyatt, J.A.; Edgar, K.J.; Schaefer, U.F.; Lehr, C.M. Mol. Pharm.2007, 4, 465-474.

[37] Collnot, E.M.; Baldes, C.; Schaefer, U.F.; Edgar, K.J.; Wempe, M.F.; Lehr, C.M. Mol. Pharm. 2010, 7, 642-651.

[38] Li, H.Y.; Miao, X.P.; Hou, M. West China Med. J. 2008, 23, 1226-1227.

[39] Mi, Y.; Liu, Y.T.; Feng, S.S. Biomaterials. 2011, 32, 4058-4066.

[40] Neuzil, J.; Dyason, J.C.; Freeman, R.; Dong, L.F.; Prochazka, L.; Wang, X.F.; Scheffler, I.; Ralph, S.J. J. Bioenerg. Biomembr. 2007, 39, 65-72.

[41] Quin, J.; Engle, D.; Litwiller, A.; Peralta, E.; Grasch, A.; Boley, T.; Hazelrigg, S. J. Surg. Res. 2005, 127, 139-143.

[42] Zhao, S.; Tan, S.W.; Guo, Y.Y.; Huang, J.; Chu, M.; Liu, H.D.; Zhang, Z.P. Biomacromolecules. 2013, 14, 2636-2646.

叶酸与TPGS修饰的负载多西他赛的DSPE-PEG胶束的制备和抗耐药肿瘤研究

Preparation and anti-MDR tumors study of folate and TPGS dual-modified DSPE-PEG micelles loaded with docetaxel

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	陆益奔, 张苗, 郑永军, 侯昕宇, 贺牧野, 楼开炎, 高峰. 基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体[J]. 中国药学(英文版), 2021, 30(12): 941-955.
[2]	刘琦, 王乐淇, 胡新平, 周楚杭, 唐颖蔚, 马翊宁, 王骁潇, 刘艳. 去氧胆酸修饰的聚合物胶束的构建及其跨膜转运的研究[J]. 中国药学(英文版), 2021, 30(1): 17-26.
[3]	周楚杭, 胡新平, 刘琦, 王乐淇, 周远航, 靳尧, 刘艳. 增强抗肿瘤药物肿瘤靶向性递送的叶酸修饰的pH敏感聚合物胶束[J]. 中国药学(英文版), 2020, 29(9): 626-636.
[4]	刘少静, 秦蓓, 韩红芳, 李立, 余丽丽, 徐小静. 硅胶柱层析和半制备液相色谱法从曲克芦丁母液中分离制备高纯度曲克芦丁及有关物质[J]. 中国药学(英文版), 2020, 29(7): 487-493.
[5]	雷萌, 王雪源, 苗航, 王佳, 沙思佳, 朱姜, 朱永强. 叶酸靶向聚合物纳米粒共传输紫杉醇和吉西他滨用于乳腺癌的治疗[J]. 中国药学(英文版), 2020, 29(10): 701-710.
[6]	靳尧, 刘琦, 周楚杭, 韩诗迪, 周远航, 胡新平, 王乐淇, 刘艳. 提高难溶药物小肠吸收的靶向寡肽转运体PepT1的聚合物胶束的制备与表征[J]. 中国药学(英文版), 2019, 28(8): 561-570.
[7]	邹洋, 靳尧, 周远航, 何楚瑜, 邓运强, 韩诗迪, 周楚杭, 李馨儒, 周艳霞, 刘艳. 双重pH敏感的聚合物-阿霉素偶联物胶束的制备与表征[J]. 中国药学(英文版), 2018, 27(8): 530-539.
[8]	何楚瑜, 靳尧, 邓运强, 邹洋, 韩诗迪, 周楚杭, 周远航, 李馨儒, 周艳霞, 刘艳. 靶向小肠转运体的聚合物胶束的制备与表征[J]. 中国药学(英文版), 2018, 27(7): 490-497.
[9]	孟帅, 崔巍, 林少辉, 王桂玲, 黑玉, 邓博, 马爽, 张展, 刘迎春, 谢英. 用于肺部给药的布地奈德白蛋白纳米粒中的分子相互作用[J]. 中国药学(英文版), 2018, 27(6): 415-428.
[10]	陆振宇, 徐蓉, 戴巍, 林晶, 沈忱. 兰索拉唑冻干粉针制备工艺及稳定性研究[J]. 中国药学(英文版), 2018, 27(6): 442-450.
[11]	蔡雁, 戴巍, 钦富华, 孙洁胤, 魏瑞龙. 染料木黄酮泊洛沙姆P407/P403混合胶束的制备及药动学研究[J]. 中国药学(英文版), 2018, 27(5): 342-351.
[12]	卜英子, 沐黎敏, 刘磊, 吕万良. 叶酸偶联表阿霉素脂质体的构建及其增强侵袭性乳腺癌细胞摄取和核定位效应的研究[J]. 中国药学(英文版), 2018, 27(4): 229-240.
[13]	刘园, 陈亚, 胡建星, 刘振明, 张亮仁. 基于药效团模型的人多药耐药相关蛋白内源性底物的预测[J]. 中国药学(英文版), 2017, 26(8): 545-555.
[14]	屈小又, 邹洋, 靳尧, 周远航, 王子琪, 何楚瑜, 邓运强, 李馨儒, 周艳霞, 刘艳. 紫杉醇的聚(2-乙基-2-噁唑啉)-维生素E琥珀酸酯pH敏感聚合物胶束的制备与体外表征[J]. 中国药学(英文版), 2017, 26(8): 582-588.
[15]	蔡彤, 裴宇盛, 张国来, 陈晨, 高华. 第8批细菌内毒素国家标准品的建立[J]. 中国药学(英文版), 2017, 26(10): 771-774.