cRGD-DOX自组装纳米粒与贝伐珠单抗联合治疗乳腺癌

doi:10.5246/jcps.2019.09.060

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (9): 627-640.DOI: 10.5246/jcps.2019.09.060

cRGD-DOX自组装纳米粒与贝伐珠单抗联合治疗乳腺癌

王雪玲¹, 梁艳琴¹, 张元³, 何冰^1,2, 代文兵¹, 张华¹, 王学清^1*, 张强^1,2*

1. 北京大学医学部药学院分子药剂学和药物递送系统北京重点实验室, 北京 100191
2. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
3. 罗德岛大学药学院生物医学和药学系, 金斯敦, 罗德岛 02881

收稿日期:2019-05-10 修回日期:2019-05-27 出版日期:2019-09-30 发布日期:2019-06-20
通讯作者: Tel.: +86-10-82802791; +86-10-82805935, E-mail: zqdodo@bjmu.edu.cn; wangxq@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81690264), the National Key Research and Development Program of China (Grant No. 2017YFA0205600) and Beijing Natural Science Foundation (Grant No. 7162108).

Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer

Xueling Wang¹, Yanqin Liang¹, Yuan Zhang³, Bing He¹, Wenbing Dai¹, Hua Zhang¹, Xueqing Wang^1*, Qiang Zhang^1,2*

1. Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
3. Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.

Received:2019-05-10 Revised:2019-05-27 Online:2019-09-30 Published:2019-06-20
Contact: Tel.: +86-10-82802791; +86-10-82805935, E-mail: zqdodo@bjmu.edu.cn; wangxq@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81690264), the National Key Research and Development Program of China (Grant No. 2017YFA0205600) and Beijing Natural Science Foundation (Grant No. 7162108).

摘要/Abstract

摘要：

肿瘤微环境中不同细胞群之间的相互作用能够促进肿瘤生长, 靶向不同细胞群可以提高肿瘤的治疗效果。整合素高表达于多种肿瘤细胞表面, 血管内皮生长因子(VEGF)对肿瘤新生血管生长具有强烈的促进作用。因此, 本研究针对肿瘤细胞和新生血管制备了一种靶向于整合素的阿霉素偶联药物(cRGD-DOX)纳米粒, 并将其与抗VEGF抗体贝伐珠单抗联合应用, 在整合素高表达的MDA-MB-231肿瘤模型上考察其抗肿瘤效果。细胞水平研究结果表明, cRGD-DOX纳米粒可以被MDA-MB-231细胞摄取, 其摄取与整合素表达相关; 与游离阿霉素相比, cRGD-DOX纳米粒的细胞毒下降; 贝伐珠单抗在1 mg/mL以下无明显的细胞毒。体内研究结果表明, 贝伐珠单抗可以降低肿瘤间质液压; 与单制剂组相比, cRGD-DOX纳米粒和贝伐珠单抗联用后药效增强。总之, 联合应用靶向新生血管的抗体药物和靶向整合素的细胞毒药物纳米粒是一个有效的抗肿瘤治疗方案。

关键词: cRGD-DOX, 自组装纳米粒, 贝伐珠单抗, 联合治疗, 乳腺癌

Abstract:

The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression. Targeting to different cell populations might result in improved therapeutic effects on malignant tumors. Integrins high express on many kinds of tumor cells, and VEGF has a strong effect on tumor angiogenesis. Therefore, based on tumor cells and angiogenesis, we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab. We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model. The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin; cRGD-DOX nanoparticles showed less cytotoxic than free DOX; Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL. The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure; the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments. These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.

Key words: RGD-DOX, Self-assembled nanoparticles, Bevacizumab, Combination therapy, Breast cancer

中图分类号:

R943

Supporting:

王雪玲, 梁艳琴, 张元, 何冰, 代文兵, 张华, 王学清, 张强. cRGD-DOX自组装纳米粒与贝伐珠单抗联合治疗乳腺癌[J]. 中国药学(英文版), 2019, 28(9): 627-640.

Xueling Wang, Yanqin Liang, Yuan Zhang, Bing He, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang. Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(9): 627-640.

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cRGD-DOX自组装纳米粒与贝伐珠单抗联合治疗乳腺癌

Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer

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