目的 制备还原响应的双氢青蒿素(DHA)前药自组装纳米粒,并对药动学行为进行评价。方法 设计合成以二硫键为连接臂的双氢青蒿素前药,采用分子自组装技术制备DHA前药自组装纳米粒(DSCNs),筛选出较优处方,考察其制剂学性质并对其药动学进行评价。结果 DSCNs粒径均一,外观圆整,包封率、载药量、粒径、PDI和Zeta电位分别为(96.75±0.03)%,(80.62±2.63)%,(128.5±3.0)nm,(0.151±0.044)和(-16.6±0.9)mV。优化后的处方放置12周后仍较较为稳定。体外释放研究中,前药中DHA的释放随着谷胱甘肽(GSH)浓度的增加而增加。药动学研究表明,DSCNs可以显著提高DHA的血液浓度。 结论 优化后的制剂能显著提高药物的稳定性及血液循环时间,为青蒿素类药物新型自组装纳米粒的抗肿瘤应用提供试验依据。
Abstract
OBJECTIVE To prepare the self-assembled nanoparticles of the reduction-response dihydroartemisinin prodrug and study its pharmacokinetics. METHODS Dihydroartemisinin as raw material, lauryl as the carrier, a dihydroartemisinin prodrug was designed and synthesized with disulfide bond as a connected arm. Molecular self-assembled technique was adopted to prepare the self-assembled nanoparticles of the dihydroartemisinin prodrug (DSCNs). Transmission electron microscopy (TEM) observed the nanoparticles morphology. Melvin granularity instrument measured the particle size, size distribution and Zeta potential. The properties of the optimized prescription were investigated, and their pharmacokinetics were evaluated. RESULTS DSCNs were spherical with uniform size, the coating rate, drug loadings, average particle size, PDI and Zeta potential were (96.75±0.03)%, (80.60±2.6)%, (128.5±3.0) nm, (0.151±0.044) and (-16.6±0.9)mV, respectively. Vitamin E-TPGS (TPGS) was selected as the stabilizer of DSCNs to prevent the accumulation of nanoparticles, and DSCNs remained stable after 12 weeks. In vitrostudy showed that the release of DHA in prodrug was increased with the increase of the concentration of glutathione (GSH). Pharmacokinetic studies showed that DSCNs could significantly increase the blood concentration of DHA. CONCLUSION The optimized preparation has long-term stability, which could be the basis for the further application of self-assembled nanoparticles to the drug sustained release system.
关键词
双氢青蒿素 /
前药 /
自组装纳米粒 /
还原响应
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Key words
dihydroartemisinin /
prodrug /
self-assembled nanoparticle /
reduction-sensitive
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中图分类号：
R944
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参考文献
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脚注
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基金
国家自然科学基金项目资助(81373364);山西省应用基础研究计划项目资助(201701D221162);山西省高等学校科技创新项目资助(2017148);山西医科大学博士启动基金资助(03201619)
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