伐普肽修饰的纳米胶束作为递送紫杉醇至生长抑素受体过表达肿瘤的靶向载体研究

doi:10.5246/jcps.2015.08.064

中国药学(英文版) ›› 2015, Vol. 24 ›› Issue (8): 501-513.DOI: 10.5246/jcps.2015.08.064

伐普肽修饰的纳米胶束作为递送紫杉醇至生长抑素受体过表达肿瘤的靶向载体研究

侯文杰, 郑华, 王坚成^*

北京大学医学部药学院药剂学系, 北京 100191

收稿日期:2015-05-03 修回日期:2015-05-15 出版日期:2015-08-22 发布日期:2015-05-20
通讯作者: Tel.: 86-10-82805932; E-mail: wang-jc@bjmu.edu.cn
基金资助:
National Basic Research Program of China (973 Program, Grant No. 2013CB932501), NSFC projects (Grant No. 81273455 and 81473158), and Programs from Ministry of Education (Grant No. NCET-11-0014 and BMU20110263).

Vapreotide-modified nanomicelle as a targeted nanocarrier for delivering paclitaxel to the tumors with overexpression of somatostatin receptors

Wenjie Hou, Hua Zheng, Jiancheng Wang^*

Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2015-05-03 Revised:2015-05-15 Online:2015-08-22 Published:2015-05-20
Contact: Tel.: 86-10-82805932; E-mail: wang-jc@bjmu.edu.cn
Supported by:
National Basic Research Program of China (973 Program, Grant No. 2013CB932501), NSFC projects (Grant No. 81273455 and 81473158), and Programs from Ministry of Education (Grant No. NCET-11-0014 and BMU20110263).

摘要/Abstract

摘要：

生长抑素受体在肿瘤细胞中有广泛表达。伐普肽(Vapreotide, VAP)作为生长抑素类似物, 因其具有与生长抑素受体高度亲和力而被用作肿瘤靶向递送系统的修饰物。本研究针对伐普肽结构中D-苯丙氨酸的外环α-NH₂与NHS-PEG-DSPE进行特异性化学偶联得到导向化合物DSPE-PEG-VAP, 并利用其修饰载紫杉醇纳米胶束给药系统。研究结果表明, 靶向配体修饰和未修饰的两种载药系统具有相似的粒径大小、表面电势、药物包载效率以及药物释放行为。在人乳腺癌MCF-7细胞模型评价中, 靶向组比非靶向组具有更高的细胞摄取量; 体内肿瘤模型中靶向组也表现出较高的肿瘤组织药物蓄积量和更优的肿瘤治疗效应。因此, 我们认为这种伐普肽修饰的纳米胶束将成为向生长抑素受体高表达的肿瘤靶向递送抗肿瘤药物的一种有潜力的载药系统。

关键词: 生长抑素受体, 伐普肽, 靶向纳米胶束, 紫杉醇, 肿瘤治疗

Abstract:

Somatostatin receptors (SSTRs) were widely expressed in many tumor cells. As a somatostatin analogue, vapreotide (VAP) can be exploited as a modifier for targeting tumor therapy based on its high affinity to SSTR. In this study, we conjugated α-NH₂of exocyclic D-phenylalanine (D-Phe) of vapreotide to N-hydroxysuccinimidyl-PEG₂₀₀₀-DSPE (NHS-PEG-DSPE), and the resulted DSPE-PEG-VAP was used as a targeting component to construct the targeted micelles for delivering paclitaxel (VAP-M-PTX) through a thin-film hydration method. Similar particle size, zeta potential, drug encapsulation efficiencies, drug release behaviors and hemolysis effects were observed between the targeted micelles (VAP-M-PTX) and the non-targeted micelles (M-PTX). In MCF-7 cells, significantly higher intracellular fluorescence intensity (1.5-fold) was determined by flow cytometry after incubation of coumarin-6 loaded targeted micelles (VAP-M-Cou) for 3 h compared with non-targeted micelles (M-Cou), and similar finding was observed confocal microscopy. Furthermore, in comparison with non-targeted formulations, higher antitumorefficacy and higher drug accumulation were found in MCF-7 tumors in nude mice after intravenous injection of the targeted micelles. In conclusion, we believed that the vapreotide-modified nanomicelles could be a promising targeted nanocarrier for delivering anticancer drugs to the tumors with overexpression of somatostatin receptors.

Key words: Somatostatin receptor, Vapreotide, Targeted nanomicelle, Paclitaxel, Tumor therapy

中图分类号:

R945

Supporting:

侯文杰, 郑华, 王坚成. 伐普肽修饰的纳米胶束作为递送紫杉醇至生长抑素受体过表达肿瘤的靶向载体研究[J]. 中国药学(英文版), 2015, 24(8): 501-513.

Wenjie Hou, Hua Zheng, Jiancheng Wang. Vapreotide-modified nanomicelle as a targeted nanocarrier for delivering paclitaxel to the tumors with overexpression of somatostatin receptors[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(8): 501-513.

参考文献

[1] Cai, S.; Vijayan, K.; Cheng, D.; Lima, E.M.; Discher, D.E. Pharm. Res. 2007, 24, 2099-2109.

[2] Lin, J.; Zhang, S.; Chen, T.; Lin, S.; Jin, H. Int. J. Pharm. 2007, 336, 49-57.

[3] Gaur, U.; Sahoo, S.K.; De, T.K.; Ghosh, P.C.; Maitra, A.; Ghosh, P.K. Int. J. Pharm. 2000, 202, 1-10.

[4] Kataoka, K.; Harada, A.; Nagasaki, Y. Adv. Drug Deliv. Rev. 2001, 47, 113-131.

[5] Savic, R.; Luo, L.; Eisenberg, A.; Maysinger, D. Science. 2003, 300, 615-618.

[6] Matsumura, Y.; Maeda, H. Cancer Res. 1986, 46, 6387-6392.

[7] Matsumura, Y. Adv. Drug Deliv. Rev. , 60, 899-914.2008

[8] Plummer, R.; Wilson, R.H.; Calvert, H.; Boddy, A.V.; Griffin, M.; Sludden, J.; Tilby, M.J.; Eatock, M.; Pearson, D.G.; Ottley, C.J.; Matsumura, Y.; Kataoka, K.; Nishiya, T. Br. J. Cancer. 2011, 104, 593-598.

[9] Danson, S.; Ferry, D.; Alakhov, V.; Margison, J.; Kerr, D.; Jowle, D.; Brampton, M.; Halbert, G.; Ranson, M. Br. J. Cancer. 2004, 90, 2085-2091.

[10] Mahmud, A.; Xiong, X.B.; Aliabadi, H.M.; Lavasanifar, A. J. Drug Target. 2007, 15, 553-584.

[11] Cai, L.L.; Liu, P.; Li, X.; Huang, X.; Ye, Y.Q.; Chen, F.Y.; Yuan, H.; Hu, F.Q.; Du, Y.Z. Int. J. Nanomedicine. , 6, 3499-3508.2011

[12] Niu, R.; Zhao, P.; Wang, H.; Yu, M.; Cao, S.; Zhang, F.; Chang, J. J. Drug Target. 2011, 19, 373-381.

[13] Li, X.; Ding, L.; Xu, Y.; Wang, Y.; Ping, Q. Int. J. Pharm. 2009, 373, 116-123.

[14] Lee, H.; Hu, M.; Reilly, R.M.; Allen, C. Mol. Pharm. 2007, 4, 769-781.

[15] Zhang, J.; Jin, W.; Wang, X.; Wang, J.; Zhang, X.; Zhang, Q. Mol. Pharm. 2010, 7, 1159-1168.

[16] Olsen, J.O.; Pozderac, R.V.; Hinkle, G.; Hill, T.; O’Dorisio, T.M.; Schirmer, W.J.; Ellison, E.C.; O'Dorisio, M.S. Semin. Nucl. Med. 1995, 25, 251-261.

[17] Engel, J.B.; Schally, A.V.; Dietl, J.; Rieger, L.; Honig, A. Mol. Pharm. 2007, 4, 652-658.

[18] Nagy, A.; Schally, A.V.; Halmos, G.; Armatis, P.; Cai, R.Z.; Csernus, V.; Kovacs, M.; Koppan, M.; Szepeshazi, K.; Kahan, Z. Proc. Natl. Acad. Sci. USA. , 95, 1794-1799.1998

[19] Huang, C.M.; Wu, Y.T.; Chen, S.T. Chem. Biol. 2000, 7, 453-461.

[20] Moody, T.W.; Fuselier, J.; Coy, D.H.; Mantey, S.; Pradhan, T.; Nakagawa, T.; Jensen, R.T. Peptides. 2005, 26, 1560-1566.

[21] Sun, L.C.; Luo, J.; Mackey, L.V.; Fuselier, J.A.; Coy, D.H. Cancer Lett. 2007, 246, 157-166.

[22] Coy, D.H.; Taylor, J. Metabolism. 1996, 45, 21-23.

[23] Weckbecker, G.; Raulf, F.; Stolz, B.; Bruns, C. Pharmacol. Ther. 1993, 60, 245-264.

[24] Yuan, M.; Wang, J.; Deng, J.; Wang, Z.; Yang, W.; Li, G.; Ren, B. Nucl. Med. Biol. 2010, 37, 317-326.

[25] Sun, L.C.; Coy, D.H. Curr. Drug Deliv. 2011, 8, 2-10.

[26] Morpurgo, M.; Monfardini, C.; Hofland, L.J.; Sergi, M.; Orsolini, P.; Dumont, J.M.; Veronese, F.M. Bioconjug. Chem. 2002, 13, 1238-1243.

[27] Zhang, Y.; Zhang, H.; Wang, X.; Wang, J.; Zhang, X.; Zhang, Q. Biomaterials. 2012, 33, 679-691.

[28] Zhao, B.J.; Ke, X.Y.; Huang, Y.; Chen, X.M.; Zhao, X.; Zhao, B.X.; Lu, W.L.; Lou, J.N.; Zhang, X.; Zhang, Q. J. Drug Target. 2011, 19, 382-390.

[29] Diaz-Mochon, J.J.; Bialy, L.; Bradley, M. Org. Lett. 2004, 6, 1127-1129.

[30] Gaucher, G.; Dufresne, M.H.; Sant, V.P.; Kang, N.; Maysinger, D.; Leroux, J.C. J. Control. Release. 2005, 109, 169-188.

[31] Vichai, V.; Kirtikara, K. Nat. Protoc. , 1, 1112-1116.2006

[32] Kalchenko, V.; Shivtiel, S.; Malina, V.; Lapid, K.; Haramati, S.; Lapidot, T.; Brill, A.; Harmelin, A. J. Biomed. Opt. 2006, 11, 050507.

[33] Mamot, C.; Drummond, D.C.; Noble, C.O.; Kallab, V.; Guo, Z.; Hong, K.; Kirpotin, D.B.; Park, J.W. Cancer Res. 2005, 65, 11631-11638.

[34] Riezman, H.; Woodman, P.G.; van Meer, G.; Marsh, M. Cell. 1997, 91, 731-738.

[35] Yamamoto, Y.; Nagasaki, Y.; Kato, Y.; Sugiyama, Y.; Kataoka, K. J. Control. Release. 2001, 77, 27-38.

[36] Dubey, V.; Nahar, M.; Mishra, D.; Mishra, P.; Jain, N.K. J. Drug Target. 2011, 19, 258-269.

[37] Yang, R.; Meng, F.; Ma, S.; Huang, F.; Liu, H.; Zhong, Z. Biomacromolecules. 2011, 12, 3047-3055.

[38] Desmettre, T.; Devoisselle, J.M.; Mordon, S. Surv. Ophthalmol. 2000, 45, 15-27.

[39] Kawano, K.; Watanabe, M.; Yamamoto, T.; Yokoyama, M.; Opanasopit, P.; Okano, T.; Maitani, Y. J. Control. Release. 2006, 112, 329-332.

[40] Basile, L.; Pignatello, R.; Passirani, C. Curr. Drug Deliv. 2012, 9, 255-268.

伐普肽修饰的纳米胶束作为递送紫杉醇至生长抑素受体过表达肿瘤的靶向载体研究

Vapreotide-modified nanomicelle as a targeted nanocarrier for delivering paclitaxel to the tumors with overexpression of somatostatin receptors

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