载阿霉素和顺铂的透明质酸纳米粒子对小鼠移植性乳腺癌的抑制作用

doi:10.13481/j.1671-587x.20180207

吉林大学学报(医学版) ›› 2018, Vol. 44 ›› Issue (02): 243-248.doi: 10.13481/j.1671-587x.20180207

载阿霉素和顺铂的透明质酸纳米粒子对小鼠移植性乳腺癌的抑制作用

马鸿云^1,2, 庄新明¹, 许维国², 刘一¹

1. 吉林大学第一医院脊柱外科, 吉林长春 130021;
2. 中国科学院长春应用化学研究所中科院生态环境高分子材料重点实验室, 吉林长春 130022

收稿日期:2017-11-05 出版日期:2018-03-28 发布日期:2018-03-30
通讯作者: 刘一,教授,主任医师,博士研究生导师(Tel:0431-81875367,E-mail:liuyi2015310@163.com) E-mail:liuyi2015310@163.com
作者简介:马鸿云(1990-),男,青海省西宁市人,在读医学硕士,主要从事骨外科学、纳米粒子抗肿瘤、乳腺癌及骨转移方面的研究。
基金资助:
国家自然科学基金面上项目资助课题（51673190）；国家自然科学基金青年科学基金资助课题（51603204）

Inhibitory effects of hyaluronic acid nanoparticles loading doxorubicin and cisplatin on allograft breast cancer in mice

MA Hongyun^1,2, ZHUANG Xinming¹, XU Weiguo², LIU Yi¹

1. Department of Spine Surgery, First Hospital, Jilin University, Changchun 130021, China;
2. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China

Received:2017-11-05 Online:2018-03-28 Published:2018-03-30

摘要/Abstract

摘要： 目的：探讨肿瘤CD44受体靶向的载阿霉素和顺铂的透明质酸（HA）纳米粒子HA_CDDP-DOX在乳腺癌治疗中的应用，阐明HA_CDDP-DOX对小鼠移植性乳腺癌的抑制作用。方法：通过绿色合成途径合成乳腺癌靶向的载药HA纳米粒子HA_CDDP-DOX，并测定其粒径、不同pH值条件下的稳定性及搭载阿霉素的释放情况。于小鼠乳腺脂肪垫接种4T1细胞，构建乳腺癌肿瘤模型。根据肿瘤体积和体质量将小鼠随机分为对照组、DOX/CDDP组和HA_CDDP-DOX组，于肿瘤生长至80 mm³后的第1、5和9天通过尾静脉注射PBS、游离混合药物DOX/CDDP和HA_CDDP-DOX进行治疗。通过检测肿瘤体积、小鼠体质量变化和免疫组织病理学等指标评价HA_CDDP-DOX对小鼠乳腺癌的抑制效果及生物安全性。利用生物荧光成像技术观察HA_CDDP-DOX在小鼠体内的药物组织分布情况。结果：HA_CDDP-DOX纳米粒子的平均粒径为（80.0±17.4） nm，pH值为7.4条件下稳定；在酸性条件下粒径增大，可有效释放DOX。抑瘤实验，与DOX/CDDP组比较，HA_CDDP-DOX组小鼠体质量增加（P<0.05），肿瘤体积减小（P<0.05）。HE染色，对照组小鼠肝脏存在肿瘤转移灶，且肺泡间隔增宽；DOX/CDDP组和HA_CDDP-DOX组肿瘤组织均有坏死，HA_CDDP-DOX组肿瘤组织的坏死程度明显重于DOX/CDDP组。与DOX/CDDP组比较，HA_CDDP-DOX组Caspase-3活性明显升高（P<0.01），而Ki-67活性明显下降（P<0.01）。生物荧光成像，HA_CDDP-DOX能够通过靶向作用有效聚集于肿瘤部位释放药物。结论：HA_CDDP-DOX纳米粒子可以有效靶向于乳腺癌细胞，降低化疗药物系统毒性，同时增强乳腺癌治疗效果。

关键词: 靶向治疗, 透明质酸, 阿霉素, 乳腺肿瘤, pH-响应性纳米粒子, 顺铂, 化学疗法

Abstract: Objective:To investigate the application of CD44 receptor-targeted nanoparticles HA_CDDP-DOX in the treatment of breast cancer, and to clarify its inhibitory effect on allograft breast cancer in the mice. Methods: Hyaluronic acid (HA) was used to construct a breast cancer targeted nanoparticle via green synthesis approach, and its particle size, stability and doxorubicin release profile at different pH conditions were measured. Then the breast cancer models were constructed by inoculating 4T1 cells into the mouse mammary fat pad. The model mice were randomly divided into control group, DOX/CDDP group and HA_CDDP-DOX group according to the tumor volumes and the body weights. PBS, free drug DOX/CDDP and HA_CDDP-DOX were intravenously injected into the allograft breast cancer models on the 1st, 5th and 9th days after the tumor volume reached about 80 mm³. The antitumor effect and biosafety of HA_CDDP-DOX were evaluated by detecting the tumor volume, mouse weight and immunohistopathology. Moreover, the biological distribution of HA_CDDP-DOX in the mice was studied by biofluorescence imaging. Results: The average particle size of HA_CDDP-DOX was (80.0 ±17.4) nm, which was stable under pH 7.4. Under acidic condition, the particle size was increased and the DOX was effectively released. Compared with DOX/CDDP group, the body weight of the mice in HA_CDDP-DOX group was increased (P<0.05) and the tumor volume was decreased (P<0.05). The HE staining results showed that the liver of the mice in control group had tumor metastasis and the alveolar septum was widened. The tumor tissue of the mice in DOX/CDDP group and HA_CDDP-DOX group were all necrotic, while in HA_CDDP-DOX group the degree of necrosis was significantly higher than DOX/CDDP group. Compared with DOX/CDDP group, the activity of Caspase-3 in HA_CDDP-DOX group was significantly increased (P<0.01), while the Ki-67 activity was significantly decreased (P<0.01). The biofluorescence imaging showed that the nanoparticle HA_CDDP-DOX could accumulate to the tumor site by targeting, and effectively release the drug. Conclusion: HA_CDDP-DOX nanoparticles can effectively target the breast cancer cells, reduce the toxicity of chemotherapy drugs, and enhance the therapeutic effect of breast cancer.

Key words: pH-sensitive nanoparticles, breast neoplasms, chemotherapy, hyaluronic acid, doxorubicin, cisplatin, targeted therapy

中图分类号:

R737.9

马鸿云, 庄新明, 许维国, 刘一. 载阿霉素和顺铂的透明质酸纳米粒子对小鼠移植性乳腺癌的抑制作用[J]. 吉林大学学报(医学版), 2018, 44(02): 243-248.

MA Hongyun, ZHUANG Xinming, XU Weiguo, LIU Yi. Inhibitory effects of hyaluronic acid nanoparticles loading doxorubicin and cisplatin on allograft breast cancer in mice[J]. Journal of Jilin University Medicine Edition, 2018, 44(02): 243-248.

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载阿霉素和顺铂的透明质酸纳米粒子对小鼠移植性乳腺癌的抑制作用

Inhibitory effects of hyaluronic acid nanoparticles loading doxorubicin and cisplatin on allograft breast cancer in mice

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