载紫杉醇的大黄酸偶联物胶束在荷瘤小鼠体内药效学研究  

Pharmacodynamics Study of Paclitaxel-loaded Rhein Conjugate Micelles in Tumor-bearing Mice

作　　者：陆伟利 欧阳惠枝 许雪雅 李崇仙 郑雅玲 王晓颖[1] 徐伟[1] LU Weili;OUYANG Huizhi;XU Xueya;LI Chongxian;ZHENG Yaling;WANG Xiaoying;XU Wei(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China)

机构地区：[1]福建中医药大学药学院,福州350122

出　　处：《中国药学杂志》2024年第7期605-611,共7页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(81603301);福建省科技厅引导性项目资助(2020Y0050)。

摘　　要：目的 研究载紫杉醇(paclitaxel, PTX)的D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS)修饰的羧甲基壳聚糖-大黄酸偶联物胶束(PTX/TPGS-CR胶束)在荷瘤小鼠体内的药效学。方法 测定PTX/TPGS-CR胶束的pH值及渗透压。采用Balb/c小鼠建立4T1皮下移植瘤模型,以Taxol^(■)作为阳性对照,以肿瘤生长曲线、抑瘤率等为主要考察指标,通过观察小鼠的体质量变化、脏器指数、病理组织HE染色切片,测定各组肿瘤组织样品P-糖蛋白(P-gp)蛋白表达情况,考察PTX/TPGS-CR胶束的安全性和有效性。结果 PTX/TPGS-CR胶束溶液的pH值与0.9%氯化钠注射液的pH值相近(5.0~7.0),渗透压为736.6~757.2 kPa。Taxol^(■)和PTX/TPGS-CR胶束低、中、高剂量组的抑瘤率分别为29.91%、20.87%、41.06%及41.84%。PTX/TPGS-CR胶束制剂的抑瘤效果优于同剂量Taxol^(■)(P<0.05),且对抑瘤效果显示剂量依赖性特征。给药期间,同等剂量下PTX/TPGS-CR胶束组小鼠体质量、器官未受到明显的影响,证明其安全性良好;肿瘤组织P-gp表达结果显示TPGS-CR胶束具有抑制P-gp表达的作用。结论 PTX/TPGS-CR胶束制剂是一种高效、低毒的纳米制剂;其具有良好的抑瘤效果,能降低PTX的毒副作用;并能通过抑制P-gp表达从而提高肿瘤细胞对PTX的敏感性,有利于肿瘤的治疗。OBJECTIVE To study the in vivo pharmacodynamics of paclitaxel-loaded TPGS-modified carboxymethyl chitosan-rhein conjugate micelles(PTX/TPGS-CR micelles)in tumor-bearing mice.METHODS The pH and osmotic pressure value of PTX/TPGS-CR micelles were determined.The 4T1 subcutaneous transplanted tumor model was established in Balb/c mice.Taxol^(■)was used as the positive control,and the tumor growth curve and tumor inhibition rate were used as the main indicators.The safety and efficacy of PTX/TPGS-CR micelles were investigated by observing the changes in body weight,organ index and pathological tissue sections of mice,and measuring the expression of P-gp protein in tumor tissues of each group.RESULTS The pH value was similar to that of 0.9%sodium chloride injection(5.0-7.0),and the osmotic pressure value was 736.6-757.2 kPa.The tumor inhibition rates of Taxol^(■)and PTX/TPGS-CR micelle in low,medium and high dose groups were 29.91%,20.87%,41.06%and 41.84%,respectively.The antitumor effect of PTX/TPGS-CR micelles was better than that of Taxol^(■)at the same dose(P<0.05),and showed a dose-dependent feature.During the administration period,the body weight and organ of the mice in the PTX/TPGS-CR micelle group at the same dose showed no significantly affected,indicating that PTX/TPGS-CR micelles had better safety.The results of P-gp expression in tumor tissue showed that TPGS-CR micelles could inhibit the expression of P-gp protein.CONCLUSION PTX/TPGS-CR micelle preparation is a nano preparation with high efficiency and low toxicity.It has a good antitumor effect and can reduce the toxicity of PTX.Moreover,it can improve the sensitivity of tumor cells to PTX by inhibiting the expression of P-gp,which is conducive to the treatment of tumors.

关 键 词：紫杉醇 聚合物胶束 大黄酸偶联物 药效学 

分 类 号：R944[医药卫生—药剂学] R969[医药卫生—药学]