中国中药杂志

2020, v.45(19) 4617-4624

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基于纳米氧化石墨烯的苦参碱原位凝胶的制备及体内药效学评价
Preparation and pharmacodynamics in vivo of nano graphene oxide-based matrine in situ gel

陈家琦;李丰;薛鹏坤;李圆圆;王莎莎;王华华;胡春月;祝侠丽;
CHEN Jia-qi;LI Feng;XUE Peng-kun;LI Yuan-yuan;WANG Sha-sha;WANG Hua-hua;HU Chun-yue;ZHU Xia-li;School of Pharmacy, Henan University of Chinese Medicine;School of Basic Medicine, Henan University of Chinese Medicine;

摘要(Abstract):

基于光敏剂纳米氧化石墨烯(NGO),以苦参碱(MAT)为模型药物,制备一种可联合肿瘤光热治疗的苦参碱原位凝胶MAT-NGO-gel,并对其理化性质和体内抗肿瘤效果进行研究。首先建立原位凝胶中苦参碱的HPLC含量测定方法。采用超声法将MAT负载于NGO表面,然后以泊洛沙姆188和泊洛沙姆407为主要材料制备MAT-NGO-gel。选择以胶凝温度为指标,筛选最佳处方工艺。最后对MAT-NGO-gel的载药量、微观形态、光热转换特性、体外释放度等方面进行表征。优化处方中泊洛沙姆188和泊洛沙姆407的质量分数分别为2%,20%,NGO与MAT的质量比为1∶1。采用最佳处方工艺制得MAT-NGO-gel胶凝温度为37.5℃,载药量为16.7%。808 nm激光照射下MAT-NGO-gel具有明显的浓度和时间依赖性光热转换特性。体外释放度结果表明,MAT-NGO-gel具有温度依赖性释药特征。以S180荷瘤小鼠为模型,结合808 nm激光进行MAT溶液、NGO-gel、MAT-NGO-gel的药效学研究。绘制实验期间荷瘤小鼠的体质量、相对瘤体积随时间的变化曲线。解剖取各组小鼠肿瘤组织,通过HE染色,观察病理学变化。与生理盐水组和空白凝胶组相比,MAT-NGO-gel组及其加激光组的荷瘤小鼠体质量增加,相对肿瘤体积增长较慢。HE染色病理切片表明MAT-NGO-gel组及其加激光组荷瘤小鼠的肿瘤细胞数量明显减少,且出现明显的细胞核破裂及溶解现象。表明MAT-NGO-gel结合808 nm激光照射具有较强的抗肿瘤活性。该实验成功制备基于纳米氧化石墨烯的苦参碱原位凝胶MAT-NGO-gel,其处方工艺稳定可行。相比于MAT溶液,MAT-NGO-gel具有明显的温度依赖性的药物缓释特性。结合808 nm近红外光照射后,MAT-NGO-gel具有更为明显的体内外抗肿瘤活性。该研究可为恶性肿瘤的多机制联合治疗提供一定的理论基础。
With matrine(MAT) as the model drug, to prepare nano graphene oxide(NGO)-based MAT in situ gel(MAT-NGO-gel), a kind of drug for tumor treatment in combination with phototheraphy, and investigate the physicochemical properties and anti-tumor effects in vivo of MAT-NGO-gel. First, HPLC method was established to measure the content of MAT in the gel. The ultrasonic method was used to load MAT onto the surface of NGO, and then poloxamer 188 and poloxamer 407 were chosen as the main materials to prepare MAT-NGO-gel. The optimum prescription was selected with the gelation temperature as the index. Finally, the drug loading rate, micromorphology, phototherrmal conversion characteristics and drug release in vitro of MAT-NGO-gel were characterized. In the optimized prescription, the concentration of poloxamer 188 and poloxamer 407 was 2% and 20% respectively, and the mass ratio of NGO and MAT was 1∶1. The gelation temperature and drug loading rate of MAT-NGO-gel prepared by the optimal prescription process was 37.5 ℃ and 16.7%. Under 808 nm laser irradiation, MAT-NGO-gel showed obvious concentration-and time-dependent photothermal conversion characteristics. In vitro release experiments showed that MAT-NGO-gel had temperature-dependent release characteristics. The pharmacodynamics of MAT solution, NGO-gel and MAT-NGO-gel were studied by using S180 tumor-bearing mice and 808 nm laser. The relative tumor volume and body weight of the tumor-bearing mice were plotted over time. After the experiment, the tumor tissues of each group were taken and the histopathological changes were observed by HE staining. The results of pharmacodynamic studies demonstrated that when compared with NS group and NGO-gel group, the body weights of mice in MAT-NGO-gel group and MAT-NGO-gel + laser group were higher, and the relative tumor volume growth was slower. The results of HE stained pathological sections showed that the tumor cells count for the mice in MAT-NGO-gel group and MAT-NGO-gel + laser group was significantly reduced, with obvious nuclear fragmentation and nucleolysis in these two groups. These results suggested that MAT-NGO-gel, especially combined with 808 nm laser, had stronger anti-tumor activity in vivo. The prescription process of MAT-NGO-gel in this experiment was stable and feasible. As compared with MAT solution, MAT-NGO-gel showed obvious sustained and temperature-dependent drug release characteristics. MAT-NGO-gel had much more obvious anti-tumor activity in vivo when combined with 808 nm laser irradiation. This study could provide certain theoretical basis for the therapy of malignant tumor with multiple mechanisms.

关键词(KeyWords): 苦参碱;纳米氧化石墨烯;原位凝胶;药效学;肿瘤
matrine;nano graphene oxide;in situ gel;pharmacodynamics;tumor

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81803740);; 河南省大学生创新训练项目(S201910471017-1);; 河南中医药大学大学生创新学习项目(CXXM[2019]0030)

作者(Author): 陈家琦;李丰;薛鹏坤;李圆圆;王莎莎;王华华;胡春月;祝侠丽;
CHEN Jia-qi;LI Feng;XUE Peng-kun;LI Yuan-yuan;WANG Sha-sha;WANG Hua-hua;HU Chun-yue;ZHU Xia-li;School of Pharmacy, Henan University of Chinese Medicine;School of Basic Medicine, Henan University of Chinese Medicine;

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