载siRNA的壳聚糖外壳磷酸钙纳米粒治疗宫颈癌研究

doi:10.5246/jcps.2018.08.053

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (8): 517-529.DOI: 10.5246/jcps.2018.08.053

• 【研究论文】 • 下一篇

载siRNA的壳聚糖外壳磷酸钙纳米粒治疗宫颈癌研究

李飘飘¹, 闫仪¹, 张海涛^1,2, 王茹¹, 韩壶壶¹, 王坚成^1*

1. 北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 中南大学药学院, 湖南长沙 410013

收稿日期:2018-05-13 修回日期:2018-06-19 出版日期:2018-09-04 发布日期:2018-06-30
通讯作者: Tel.: +86-010-82805932, E-mail: wang-jc@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81473158, 81690264 and 81773650), the New Drug R&D program of China (Grant No. 2018ZX09721003-004) and the Opening Project of Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education (Sichuan University).

Treatment of cervical cancer by siRNA-loaded chitosan-coated calcium phosphate nanoparticles

Piaopiao Li¹, Yi Yan¹, Haitao Zhang^1,2, Ru Wang¹, Huhu Han¹, Jiancheng Wang^1*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China

Received:2018-05-13 Revised:2018-06-19 Online:2018-09-04 Published:2018-06-30
Contact: Tel.: +86-010-82805932, E-mail: wang-jc@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81473158, 81690264 and 81773650), the New Drug R&D program of China (Grant No. 2018ZX09721003-004) and the Opening Project of Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education (Sichuan University).

摘要/Abstract

摘要：

本研究设计构建一种壳聚糖包被的磷酸钙纳米粒子(CS/CaP /siRNA)递送siRNA用于宫颈癌治疗。通过纳米沉淀法制备得到均一球形的CS/CaP/siRNA纳米粒,其粒径约为194 nm, ζ电位约为+27 mV。体外实验证明该纳米粒可以有效地递送siEGFR到Hela细胞中并显著下调EGFR表达水平,这可能与壳聚糖的细胞粘附性增强而延长了细胞摄取时间有关。此外,被摄取进入胞内的纳米粒表现出pH响应性纳米粒子膨胀最后解散导致siRNA释放从而促进siRNA从溶酶体快速地逃逸到胞浆内。此外,裸鼠异位接种宫颈癌瘤内注射疗效结果显示CS/CaP/siEGFR纳米粒具有高效的肿瘤生长抑制效应,且整个实验期间体重无明显变化。所有这些结果表明CS/CaP/siRNA纳米粒将有可能通过粘膜给药方式治疗宫颈癌。

关键词: 小干扰核酸递送, 壳聚糖, 磷酸钙, pH敏感性, 宫颈癌

Abstract:

In the present study, a chitosan-coated calcium phosphate nanoparticle (CS/CaP/siRNA NP) was developed to deliver siRNA for treatment of cervical cancer. The CS/CaP/siRNA NPs were prepared by the nano-precipitation method. The resulted NPs had a uniform spherical morphology with a size of ~194 nm and a zeta potential of ~+27 mV. In vitro experiments demonstrated that these NPs could efficiently deliver siEGFR into Hela cells and significantly down-regulate the EGFR expression level, which was probably associated with enhanced cell adhesion of chitosan, leading to extended residence time of cell internalization. Then the internalized CS/CaP/siRNA NPs exhibited pH-responsive disassembly of NPs, resulting in the enhanced release of siRNA and rapid lysosomal escape into cytoplasm. Moreover, in vivo anticancer results showed that the CS/CaP/siRNA NPs had significant inhibitory effects on tumor growth after intratumoral injection in Hela tumor xenografted nude mice, accompanying with no obvious changes of body weight during the whole experimental period. All these results indicated that the CS/CaP/siRNA NPs would have great potential to deliver siRNA for the treatment of cervical cancer via mucosal administration.

Key words: siRNA delivery, Chitosan, Calcium phosphate, pH-sensitive, Cervical cancer

中图分类号:

R944

Supporting:

李飘飘, 闫仪, 张海涛, 王茹, 韩壶壶, 王坚成. 载siRNA的壳聚糖外壳磷酸钙纳米粒治疗宫颈癌研究[J]. 中国药学(英文版), 2018, 27(8): 517-529.

Piaopiao Li, Yi Yan, Haitao Zhang, Ru Wang, Huhu Han, Jiancheng Wang. Treatment of cervical cancer by siRNA-loaded chitosan-coated calcium phosphate nanoparticles[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(8): 517-529.

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载siRNA的壳聚糖外壳磷酸钙纳米粒治疗宫颈癌研究

Treatment of cervical cancer by siRNA-loaded chitosan-coated calcium phosphate nanoparticles

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