紫杉醇聚合物胶束的组织分布和生物学评价

中国临床药理学与治疗学 ›› 2017, Vol. 22 ›› Issue (11): 1207-1214.

紫杉醇聚合物胶束的组织分布和生物学评价

姚天怡¹, 尹少平¹, 刘雯¹, 赵炎磊², 王广基², 李娟¹

¹中国药科大学药学院药剂系，南京 210009，江苏；²中国药科大学药物代谢动力学重点实验室，南京 210009，江苏

收稿日期:2017-05-19 修回日期:2017-10-16 出版日期:2017-11-26 发布日期:2017-12-11
通讯作者: 李娟，女，教授，博士，博士生导师，研究方向：新型药用高分子材料与靶向释药系统研究。 Tel：13951619958 E-mail:lijuancpu@163.com
作者简介:姚天怡，女，硕士，研究方向：新制剂与新技术研究。 Tel：15850632285 E-mail：1282515241@qq.com
基金资助:
国家自然科学基金面上项目（81373363）；国家科技部十一五重大新药创制（2009ZX09310-004）；江苏省科技支撑-社会发展项目（BE2010723）；江苏省研究生创新工程（CXLX11-0813）

Biodistribution and biological evaluation of paclitaxel polymer micelles

YAO Tianyi ¹, YIN Shaoping ¹, LIU Wen ¹, ZHAO Yanlei ², WANG Guangji², LI Juan ¹

¹ Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; ² Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, Jiangsu, China

Received:2017-05-19 Revised:2017-10-16 Online:2017-11-26 Published:2017-12-11

摘要/Abstract

摘要：

目的: 研究紫杉醇（paclitaxel,PTX）聚合物胶束的荷瘤鼠组织分布和生物安全性。方法: 采用S180荷瘤小鼠模型研究静脉注射PTX聚合物胶束和Taxol的药动学参数变化、组织分布特征和抗肿瘤作用；通过动物实验研究PTX聚合物胶束的急性毒性、溶血性和静脉刺激性。结果: PTX聚合物胶束的t1/2和平均滞留时间（MRT）分别为Taxol的3.52和4.55倍，在肿瘤部位的相对摄取率为2.31，表明该胶束具有长循环和肿瘤靶向作用。PTX聚合物胶束对S180荷瘤小鼠的抑制显著强于Taxol（P<0.05）。生物安全性评价结果显示PTX聚合物胶束的最大耐受剂量和LD50均显著高于Taxol（P<0.05），对兔耳缘静脉无明显血管刺激性。结论: PTX聚合物胶束延长了药物体内循环时间、增强了肿瘤靶向性和抗癌活性，提高了生物安全性，期望为临床提供一种高效、低毒紫杉醇聚合物胶束靶向制剂。

关键词: 紫杉醇, 聚合物胶束, 组织分布, 抗肿瘤活性, 安全性评价

Abstract:

AIM: The biodistribution in tumor-bearing mice and biosafety of paclitaxel (PTX) polymer micelles were investigated. METHODS: The pharmacokinetic study, tissue distribution and antineoplastic effect of PTX polymer micelles and Taxol were evaluated on S180 tumor-bearing mice after intravenous injection. Animals were used to research the acute toxicity, hemolysis and venous irritation of PTX polymer micelle. RESULTS:The t1/2 and MRT of PTX polymer micelles were 3.52 and 4.55 times of Taxol, respectively. Tissue distribution studies showed that the relative uptake rate of PTX polymer micelles at tumor sites was 2.31. The results indicated that PTX polymer micelles improved the circulation time and tumor targeting. The antitumor efficacy of PTX polymer micelles was significantly higher than Taxol. Maximum tolerated dose and LD50 of PTX polymer micelles were significantly improved. PTX polymer micelles had no obvious vascular irritation to ear vein of rabbits. CONCLUSION: The circulation time, tumor targeting, antineoplastic effect and biosafety of PTX polymer micelles were improved, which might turn into a promising tumor targeting paclitaxel polymer micelle preparations in clinic with maximum effect and minmum toxicity.

Key words: paclitaxel, polymer micelles, biodistribution, antitumor efficacy, safety study

中图分类号:

R965.2

姚天怡, 尹少平, 刘雯, 赵炎磊, 王广基, 李娟. 紫杉醇聚合物胶束的组织分布和生物学评价[J]. 中国临床药理学与治疗学, 2017, 22(11): 1207-1214.

YAO Tianyi, YIN Shaoping, LIU Wen, ZHAO Yanlei, WANG Guangji, LI Juan. Biodistribution and biological evaluation of paclitaxel polymer micelles[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(11): 1207-1214.

参考文献

［1］Lammers T, Kiessling F, Hennink WE, et al. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress［J］. J Control Release, 2012, 161(2): 175-187.
［2］Wei J, Li Y, Wang M, et al. A systematic investigation of the formation of ordered mesoporous silicas using poly (ethylene oxide)-b-poly (methyl methacrylate) as the template［J］. J Materials Chemistry A, 2013, 1(31): 8819-8827.
［3］姬时宇, 胡毅. 白蛋白结合型紫杉醇治疗晚期原发性肝癌的效果观察简［J］. 临床肝胆病杂志, 2016,32(10): 1911-1915.
［4］Zhang C, Qu G, Sun Y, et al. Biological evaluation of N-octyl-O-sulfate chitosan as a new nano-carrier of intravenous drugs［J］. Eur J Pharm Sci, 2008, 33(4): 415-423.
［5］Zhao Y, Li J, Yu H, et al. Synthesis and characterization of a novel polydepsipeptide contained tri-block copolymer (mPEG-PLLA-PMMD) as self-assembly micelle delivery system for paclitaxel［J］. Int J Pharm, 2012, 430(1): 282-291.
［6］Wei Y, Xue Z, Ye Y, et al. Pharmacokinetic and tissue distribution of paclitaxel in rabbits assayed by LC‐UV after intravenous administration of its novel liposomal formulation［J］. Biomed Chromatogr, 2014, 28(2): 204-212.
［7］Mishra GP, Doddapaneni BS, Nguyen D, et al. Antiangiogenic effect of docetaxel and everolimus as individual and dual-drug-loaded micellar nanocarriers［J］. Pharm Res, 2014, 31(3): 660-669.
［8］Zhang P, Hu L, Yin Q, et al. Transferrin-conjugated polyphosphoester hybrid micelle loading paclitaxel for brain-targeting delivery: synthesis, preparation and in vivo evaluation［J］. J Control Release, 2012, 159(3): 429-434.
［9］刘奕明, 林爱华, 邓时贵, 等. 甘草酸表面修饰阿霉素壳聚糖纳米粒在小鼠体内的组织分布［J］. 中国临床药理学与治疗学, 2010,15(1): 66-71.
［10］Xiao K, Luo J, Fowler WL, et al. A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer［J］. Biomaterials, 2009, 30(30): 6006-6016.
［11］Min KH, Kim JH, Bae SM, et al. Tumoral acidic pH-responsive MPEG-poly (β-amino ester) polymeric micelles for cancer targeting therapy［J］. J Control Release, 2010, 144(2): 259-266.
［12］Guo X, Shi C, Wang J, et al. pH-triggered intracellular release from actively targeting polymer micelles［J］. Biomaterials, 2013, 34(18): 4544-4554.
［13］王福根, 庄让笑, 沈益琴, 等. 乙酰半胱氨酸纳米微球药动学及药效学评价［J］. 中国临床药理学与治疗学, 2013, 18(2): 136-141.

[1]	郭璐, 钟振东, 韩奕岑, 石毅, 杨勇, 边原, 刘晓姝, 张静, 郎琴, 钟甜. 不同给药方式在大鼠内对利巴韦林的药代动力学和组织分布的影响[J]. 中国临床药理学与治疗学, 2022, 27(1): 25-32.
[2]	陈爱瑛, 程敏, 繆云萍, 叶小弟, 田雪君, 郑高利. 舒尼替尼药代动力学和脑肾组织分布特征[J]. 中国临床药理学与治疗学, 2020, 25(10): 1105-1110.
[3]	邢晗，宁晨，孔德璇，蔡卉，周时雨，任畅，孔颖，程钰洁，陈西敬. 高抗肿瘤活性汉黄芩素衍生物GL-V9在大鼠体内的组织分布和排泄研究[J]. 中国临床药理学与治疗学, 2019, 24(8): 889-895.
[4]	董金良. 每周脂质体紫杉醇联合替吉奥对老年晚期胃癌患者血清肿瘤标志物与可溶性E-钙黏连蛋白的影响[J]. 中国临床药理学与治疗学, 2019, 24(7): 805-809.
[5]	康辉，雍小兰，胡婷婷，储碧心，王蓝天. 国产拉科酰胺片的药动学及安全性评价[J]. 中国临床药理学与治疗学, 2019, 24(2): 192-197.
[6]	杨科，李峻岭，杜斌，田中秋，景秀娟. 白蛋白结合型紫杉醇二线及以上治疗晚期非小细胞肺癌的单臂、单中心探索性临床研究[J]. 中国临床药理学与治疗学, 2019, 24(11): 1281-1286.
[7]	郭丽，韩晨阳. 胡椒碱脂质体的制备及对于胃癌细胞体外抗肿瘤活性的作用研究[J]. 中国临床药理学与治疗学, 2018, 23(11): 1240-1245.
[8]	彭朋，元唯安，胡薏慧，汤洁，蒋健. 药物临床试验不良事件监管问题分析[J]. 中国临床药理学与治疗学, 2018, 23(1): 78-82.
[9]	童月红，邵明君，胡旻，胡美旭，张琳，竺鹏飞. UTP23基因在上皮性卵巢癌紫杉醇耐药细胞中的表达及对紫杉醇化疗耐药的影响[J]. 中国临床药理学与治疗学, 2017, 22(6): 654-658.
[10]	朱晓婕，孔颖，刘琦，卢杨，赵娣，李宁，陈西敬. 叶酸靶向多西紫杉醇纳米肺吸入粉雾剂的制备及评价[J]. 中国临床药理学与治疗学, 2017, 22(5): 495-500.
[11]	袁雅文，李岩，杨劲. LC-MS/MS法测定对氨基水杨酸浓度及在大鼠组织分布研究中的应用[J]. 中国临床药理学与治疗学, 2017, 22(3): 272-280.
[12]	刘史佳，陈都，殷俊刚，储继红，许美娟，刘芳，戴国梁，熊宁宁，居文政. 左乙拉西坦注射液与左乙拉西坦片在健康受试者中的药代动力学比较[J]. 中国临床药理学与治疗学, 2017, 22(3): 294-298.
[13]	周晓芳，黄晓龙，陈宜涛，俞欢. 枸杞多糖对紫杉醇治疗子宫内膜癌的增效减毒机制研究[J]. 中国临床药理学与治疗学, 2016, 21(12): 1354-1360.
[14]	盛莉莉，朱益平. GP方案对比GT方案一线治疗转移性三阴性乳腺癌的疗效和安全性研究[J]. 中国临床药理学与治疗学, 2016, 21(11): 1281-1287.
[15]	傅君, 叶大风, 傅云峰. 紫杉醇耐药卵巢癌细胞亚株的蛋白组学研究[J]. 中国临床药理学与治疗学, 2015, 20(5): 525-530.