Angiopep-2修饰载神经毒素介孔二氧化硅脂质囊纳米粒的制备及其体内外评价

陶成浩; 郑红月; 姚文栋; 汤红霞; 马瑞; 诸佳珍; 李范珠<sup>*</sup>

引用本文:	陶成浩,郑红月,姚文栋,汤红霞,马瑞,诸佳珍,李范珠.Angiopep-2修饰载神经毒素介孔二氧化硅脂质囊纳米粒的制备及其体内外评价[J].中国现代应用药学,2018,35(4):467-471.
	TAO Chenghao,ZHENG Hongyue,YAO Wendong,TANG Hongxia,MA Rui,ZHU Jiazhen,LI Fanzhu.Preparation and in Vitro/in Vivo Evaluation of Angiopep-2 Modifying Neurotoxin Loaded Phospholipid-Functionalized Mesoporous Silica Nanoparticles[J].Chin J Mod Appl Pharm(中国现代应用药学),2018,35(4):467-471.

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Angiopep-2修饰载神经毒素介孔二氧化硅脂质囊纳米粒的制备及其体内外评价
陶成浩, 郑红月, 姚文栋, 汤红霞, 马瑞, 诸佳珍, 李范珠
浙江中医药大学, 杭州 311402

摘要:

目的制备Angiopep-2（ANG）修饰的载神经毒素（neurotoxin，NT）介孔二氧化硅脂质囊纳米粒（mesoporous silica nanoparticles，MSN）（ANG-LP-MSN-NT），并进行体内外评价。方法利用改进的Stober法制备介孔二氧化硅纳米粒，然后运用薄膜水化法制备ANG-LP-MSN-NT。考察其形态、粒径、Zeta电位、载药量和包封率；通过小角粉末衍射、氮气吸-脱附法等技术对其进行表征；透析袋法考察其体外释药特性；热板法和醋酸扭体法考察其镇痛效果。结果制备的MSN比表面积为557 m²·g^-1，孔径和孔容积（V_p）分别为2.94 nm和0.58 cm³·g^-1。ANG-LP-MSN-NT分布均一，无团聚现象，粒径为（123.37±3.76）nm（PDI 0.20±0.02），Zeta电位为（-16.57±1.59）mV，载药量与包封率分别为（10.75±0.54）%与（91.82±3.12）%。ANG-LP-MSN-NT较MSN-NT体外突释降低，缓释特性明显；药效学实验结果表明ANG-LP-MSN-NT起效快、最大镇痛效应优于其他组别。结论 ANG-LP-MSN-NT解决了二氧化硅易团聚、易突释的问题，且更有利于NT在脑部富集，发挥更好的镇痛效果，该纳米递药系统作为神经毒素载体在镇痛方面具有较好的应用前景。

关键词: 神经毒素 Angiopep-2 介孔二氧化硅脂质囊纳米粒体内外评价

DOI：10.13748/j.cnki.issn1007-7693.2018.04.002

分类号:R944

基金项目:国家自然科学基金项目（81673607，81473361）；浙江省大学生科技创新活动计划暨新苗人才计划（2017R410056）；浙江省中医药科技计划项目（2018ZQ013）；浙江省教育厅一般科研项目（Y201431480）

Preparation and in Vitro/in Vivo Evaluation of Angiopep-2 Modifying Neurotoxin Loaded Phospholipid-Functionalized Mesoporous Silica Nanoparticles

TAO Chenghao, ZHENG Hongyue, YAO Wendong, TANG Hongxia, MA Rui, ZHU Jiazhen, LI Fanzhu

Zhejiang Chinese Medical University, Hangzhou 311402, China

Abstract:

OBJECTIVE To prepare and evaluate Angiopep-2 (ANG) modifying neurotoxin (NT) loaded phospholipid-functionalized mesoporous silica nanoparticles (MSN) (ANG-LP-MSN-NT). METHODS MSN was synthesized by modified-Stober method. MSN-NT was developed by impregnation adsorption method. ANG-LP-MSN-NT was prepared by film hydration method. Laser particle size analyzer and transmission electron microscope were used to determine the particle size, Zeta potential and morphology. Small angle X-ray diffraction was used to determine the mesoporous structure; nitrogen adsorption method was used to calculate the surface area, pore diameter and pore volume. The drug release behavior of ANG-LP-MSN-NT was studied by dialysis method. Pharmacodynamics of ANG-LP-MSN-NT was studied by the hot-plate test and the acetic acid-writhing test. RESULTS The specific surface area, pore diameter and pore volume (V_p) of MSN were 557 m²·g^-1, 2.94 nm and 0.58 cm³·g^-1, respectively. The mean particle size and Zeta potential of ANG-LP-MSN-NT were (123.37±3.76)nm with PDI 0.20±0.02 and (-16.57±1.59)mV. The drug loading and entrapment efficiency of ANG-LP-MSN-NT were (10.75±0.54)% and (91.82±3.12)%. In vitro release, compared with MSN-NT, burst release of ANG-LP-MSN-NT was smaller and sustained release was more obvious. The results of pharmacodynamics experiment showed that the onset time and the maximum effect of ANG-LP-MSN-NT were better than other groups. CONCLUSION The successful preparation of ANG-LP-MSN-NT solves the problem of aggregation and burst release of MSN and low drug loading and easy leakage of liposomes. ANG-LP-MSN-NT has profit for NT enrichment in brain and a better analgesic effect. ANG-LP-MSN is a prospective drug delivery system for neurotoxin.

Key words: neurotoxin Angiopep-2 phospholipid capping mesoporous silica nanoparticles in vivo and in vitro evaluation