药学学报, 2016, 51(9): 1476-1482
引用本文:
范菲, 唐小海, 黎霞, 冉茂盛, 李玲芳, 彭琳. 果胶多柔比星纳米混悬剂的制备及初步药效评价[J]. 药学学报, 2016, 51(9): 1476-1482.
FAN Fei, TANG Xiao-hai, LI Xia, RAN Mao-sheng, LI Ling-fang, PENG Lin. Preparation and evaluation of pharmacodynamic of the pectin-doxorubicin conjugate nanosuspensions[J]. Acta Pharmaceutica Sinica, 2016, 51(9): 1476-1482.

果胶多柔比星纳米混悬剂的制备及初步药效评价
范菲1,2, 唐小海1,2, 黎霞1, 冉茂盛2, 李玲芳2, 彭琳1,2
1. 四川师范大学生命科学学院, 四川 成都 610101;
2. 重庆莱美药业股份有限公司, 重庆 401336
摘要:
运用高压均质技术制备果胶多柔比星轭合物(pectin-doxorubicin conjugate,PDC)纳米混悬液,评价其理化性质、体外释放、体内释放及抗肿瘤活性。以纳米粒平均粒径及多分散指数(polydispersity index,PI)为指标,研究各影响因素如压力、循环次数和稳定剂种类对PDC纳米混悬剂的影响。考察PDC纳米混悬液在pH为5.1或7.4的磷酸盐缓冲液(phosphate buffer saline,PBS)中的累积释放率。腹腔注射多柔比星(doxorubicin,DOX)当量为10mg·kg-1的PDC纳米混悬液或10 mg·kg-1 DOX,测定家兔血浆中DOX浓度。构建SKOV3细胞裸鼠模型,腹腔注射DOX当量为10、5、2.5 mg·kg-1的PDC纳米混悬液,观察裸鼠生长状态。结果表明: PDC纳米混悬剂的平均粒径为118.8±6.93nm,PI为0.14±0.03,zeta电位为-27.2±0.36mV。PDC纳米混悬液在pH 7.4的PBS中基本不释放,在pH 5.1时,30h内累积释放率约40%。腹腔给药后,PDC组家兔血浆中DOX浓度低于DOX组,呈现先升高后降低的趋势,最终维持在60 ng·mL-1左右。此外,PDC纳米混悬液能有效抑制SKOV3细胞裸鼠移植瘤的生长,高剂量组裸鼠腹水瘤及瘤结节重量比阴性对照组显著减少。综上,PDC有望开发成一种高效低毒的靶向治疗癌性腹水的新型药物。
关键词:    纳米混悬剂      高压均质      卵巢癌      多柔比星      果胶多柔比星轭合物     
Preparation and evaluation of pharmacodynamic of the pectin-doxorubicin conjugate nanosuspensions
FAN Fei1,2, TANG Xiao-hai1,2, LI Xia1, RAN Mao-sheng2, LI Ling-fang2, PENG Lin1,2
1. College of Life Science, Sichuan Normal University, Chengdu 610101, China;
2. Chongqing Lummy Pharmaceutical Co., Ltd, Chongqing 401336, China
Abstract:
This study was conducted to produce pectin-doxorubicin conjugate (PDC) nanosuspensions by high-pressure homogenization, and investigating the physico-chemical properties, the cumulative release rate in vitro and in vivo, and the anti-tumor activity. The major production parameters such as pressure, cycle numbers and types of stabilizers on the mean particle size and polydispersity index (PI) of PDC nanosuspensions were investigated. The cumulative release rate in phosphate buffer saline (PBS) at pH 5.1 or 7.0 were studied. The concentration of doxorubicin (DOX) in plasma of rabbit were recorded after intraperitoneal injection of PDC nanosuspensions (DOX was equivalent to 10mg·kg-1) or DOX (10mg·kg-1). We established an animal model of the nude mice with SKOV3 cell, and injected the PDC nanosuspensions (DOX was equivalent to 10, 5, 2.5 mg·kg-1) in the first day, and observed the growth state of nude mice. The particle size of PDC nanosuspensions was 118.8±6.93 nm, PI was 0.14±0.03, as well as the zeta potential was -27.2±0.36mV. It shows that no drug release was found in PBS at pH 7.4. About 40% cumulative release was determined in PBS at 5.1 after 30 h. The concentration of DOX in plasma of PDC group was 60 ng·mL-1, and was lower than that of DOX group. Compared with control group, high-dose-group decreased the weight of nude mice's ascites tumor and burrknot. PDC nanosuspensions can inhibit the growth of SKOV3 cell line in nude mice. In summary, PDC nanosuspensions are target-specific drugs with high efficiency and low toxicity in the ascites cancer model.
Key words:    nanosuspension    high pressure homogenization    ovarian cancer    doxorubicin    pectin-doxorubicin conjugate   
收稿日期: 2016-04-16
DOI: 10.16438/j.0513-4870.2016-0357
基金项目: 国家科技重大专项资助项目(2011ZX09102-001)。
通讯作者: 唐小海
Email: pharmmateceo@aliyun.com.cn
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