Page 73 - 2021年19期

多西紫杉醇-双氢青蒿素偶联前药自组装纳米粒的稳定性、体外

释放特征及组织分布 Δ

＊
李玉洁 ，李 宁，王蓉蓉，张淑秋，任国莲（山西医科大学药学院，山西 晋中 030619）
#
中图分类号 R917；R965 文献标志码 A 文章编号 1001-0408（2021）19-2371-07
DOI 10.6039/j.issn.1001-0408.2021.19.11

摘 要 目的：研究多西紫杉醇（DTX）-双氢青蒿素（DHA）偶联前药自组装纳米粒（DTX-S-S-DHA NPs）的稳定性、体外释放特征
及组织分布。方法：采用高效液相色谱法进行DTX-S-S-DHA的体外分析；以粒径、多分散系数（PDI）和包封率（EE）为评价指标，
考察DTX-S-S-DHA NPs在不同介质[水、生理盐水、磷酸盐缓冲液（PBS，pH 7.4）和RPMI 1640培养基]中的物理稳定性和长期稳定
性；以含或不含10 mmol/L二硫苏糖醇（DTT）的30％乙醇溶液为释放介质，采用小杯法考察DTX-S-S-DHA NPs中DTX-S-S-DHA
的体外释放特征；采用小动物活体成像仪考察经DiR染料标记的DTX-S-S-DHA NPs（DTX-S-S-DHA/DiR NPs）在乳腺癌荷瘤模型
小鼠组织中的分布以及肿瘤靶向性。结果：在稳定性实验中，DTX-S-S-DHA NPs在水、生理盐水、PBS、RPMI 1640培养基中振荡
24 h内，其粒径、PDI、EE均无明显变化；在4 ℃条件下保存时，随着保存时间的增加，其在生理盐水中的粒径逐渐增大，在PBS中
的粒径逐渐减小，且在两者中的EE逐渐降低至75％以下，而在水和RPMI 1640培养基中的粒径、PDI、EE均无明显变化。在体外
释放实验中，DTX-S-S-DHA NPs 中的 DTX-S-S-DHA 在含 10 mmol/L DTT 的释放介质中基本不释放；而在不含 DTT 的释放介质
中，其 24 h 累积释放率可达 83％，符合一级动力学模型释放特征。在组织分布实验中，DTX-S-S-DHA/DiR NPs 在小鼠肿瘤组
织中的分布明显多于其他组织（心、肝、脾、肺、肾）。结论：DTX-S-S-DHA NPs在不同介质中均具有良好的物理稳定性，且在水和
RPMI 1640培养基中具有良好的长期稳定性；其在还原环境中能迅速释放出母药，具有很好的肿瘤靶向性。
关键词 多西紫杉醇；双氢青蒿素；偶联前药；自组装纳米粒；稳定性；体外释放；组织分布

Stability，in vitro Release and Tissue Distribution of Docetaxel-dihydroartemisinin Conjugated Prodrug
Self-assembled Nanoparticles
LI Yujie，LI Ning，WANG Rongrong，ZHANG Shuqiu，REN Guolian（School of Pharmacy，Shanxi Medical
University，Shanxi Jinzhong 030619，China）
ABSTRACT OBJECTIVE：To study the stability，in vivo release characteristics and tissue distribution of docetaxel（DTX）-
dihydroartemisinin （DHA） conjugated prodrug self-assembled nanoparticles （DTX-S-S-DHA NPs）. METHODS：HPLC method
was adopted to analyze DTX-S-S-DHA in vitro. The phycial and long-term stability of DTX-S-S-DHA NPs in mediums [water，
saline，phosphate buffer（PBS，pH 7.4）and RPMI 1640 medium] were investigated by using particle size，polydispersity index
（PDI）and encapsulation efficiency（EE）as evaluation indexes. The in vitro release characteristics of DTX-S-S-DHA released from
DTX-S-S-DHA NPs was also investigated with small glass method，using 30％ ethanol solution with or without 10 mmol/L
dithiothreitol（DTT）as medium. The small live animal imager was adopted to investigate the tissue distribution and tumor targeting
capability of DiR-labeled DTX-S-S-DHA NPs （DTX-S-S-DHA/DiR NPs）in breast cancer bearing mice. RESULTS：In stability
test，there was no statistical difference in particle size，PDI and EE of DTX-S-S-DHA NPs incubated in water，normal saline，PBS
and RPMI 1640 medium for 24 h. When stored at 4 ℃，with the increase of storage time，the particle size of DTX-S-S-DHA NPs
in normal saline gradually increased，while those in PBS gradually decreased；EE of both gradually decreased to less than 75％，
but there was no significant change in particle size，PDI and EE of DTX-S-S-DHA NPs in water and RPMI 1640 medium. In the in
vitro release experiments，DTX-S-S-DHA in DTX-S-S-DHA NPs was not released in the release medium containing 10 mmol/L
DTT；at 24 h，the cumulative release rate of DTX-S-S-DHA released from DTX-S-S-DHA NPs in release medium without DTT
was about 83％，which was in line with first-order kinetic model. In tissue distribution test，the distribution of DTX-S-S-DHA/DiR
NPs in tumor sites of mice was significantly more than in other tissues（heart，liver，spleen，lung and kidney）. CONCLUSIONS：
DTX-S-S-DHA NPs show good physical stability in different mediums，especially have good long-term stability in water and RPMI
1640 medium；they can quickly release the parent drug in the
Δ 基金项目：山西省平台基地和人才专项（No.201805D211002）；
山西医科大学博士启动基金资助项目（No.03201619） reduction environment and has good tumor targeting.
＊ 硕 士 研 究 生 。 研 究 方 向 ：新 剂 型 与 药 动 学 。 电 话 ：0351- KEYWORDS Docetaxel； Dihydroartemisinin； Conjugated
3985243。E-mail：13603122995@163.com prodrug；Self-assembled nanoparticles； Stability； in vitro
# 通信作者：副教授，硕士生导师，博士。研究方向：小分子抗肿 release；Tissue distribution
瘤药物新型纳米递药系统。电话：0351-3985190。E-mail：glren2007@
126.com

中国药房 2021年第32卷第19期 China Pharmacy 2021 Vol. 32 No. 19 ·2371 ·