聚乙二醇两端修饰依托泊苷及人参皂苷Rh2的自组装胶束构建及其理化性质表征  

Preparation and characterization of self-assemble micelles based on a novel polymer designed as polyethylene glycol-modified ginsenoside Rh2 and etoposide

作　　者：赵海军[1] 赵维英[1] 洪泽辉[2] 

机构地区：[1]东南大学附属中大医院妇产科,南京210009 [2]东南大学医学院遗传与发育生物学系,发育与疾病相关基因教育部重点实验室,南京210009

出　　处：《中国新药杂志》2016年第17期2027-2035,共9页Chinese Journal of New Drugs

摘　　要：目的：本研究设计1种PEG两端修饰疏水药物（人参皂苷Rh2及依托泊苷）的两亲性聚合物,并以此制备及表征其自组装成的聚合物胶束。方法：以p NP-PEG-p NP为主链框架,利用对硝基苯氧基团易于离去的特性,在无水条件下将人参皂苷Rh2及依托泊苷与PEG链两端共价连接,形成两端疏水、中间亲水的两亲性聚合物,采用水透析法制备聚合物胶束,并通过动态光散射（DLS）和透射电镜（TEM）表征胶束理化性质。结果：以此法所得的GRh2-PEG-vp16最终产率为62.9%,化学结构经1H NMR和FT-IR确证为目标聚合物;通过包埋荧光探针芘法测得GRh2-PEG-vp16的临界胶束浓度为63.4μg·m L-1;通过单因素考察确立最佳制备工艺为：37℃下,50 mg·m L-1的GRh2-PEG-vp16乙醇溶液滴入5 m L去离子水中,流动水透析8 h。制备所得的胶束粒径为（112.64±4.28）nm,多分散系数为（0.224±0.002）,Zeta电位为（-13.82±2.74）m V,在p H 4.5~7.4范围内、在50倍体积去离子水的稀释下以及同等体积胎牛血清共孵育12 h均能保持粒径、电位的相对稳定。体外释放行为研究表明,在p H 6.5条件下依托泊苷和人参皂苷Rh2的48 h累计释放量分别为42.5%和52.5%。结论：GRh2-PEG-vp16可作为一种很有前景的中西药协同抗肿瘤纳米递送系统。Objective：To synthesize an amphiphilic polymer designed as drug-PEG-drug and then use it to prepare self-assemble micelles. Methods： GRh2-PEG-vpl6 was synthesized by taking pNP-PEG-pNP as the backbone and conjugating ginsenoside Rh2 or etoposide with both ends of PEG through removing the protection groups （4-nitrophenol）. GRh2-PEG-vp16 with amphiphilic characteristics was assembled into polymeric micelles using dialysis method, and the physieochemical properties of the micelles were investigated by dynamic light scattering （DLS） and transmission electron microscope （TEM）. Results： GRh2-PEG-vp16 was synthesized successfully at a yield of 62.9% , and the chemical structure was confirmed by ＇HNMR and FT-IR. The critical mieelle concentration（CMC） was measured to be 63. 4 ug· mL-1 by entrapping pyrene method. The optimal preparation process was determined as follows：50 mg·mL-1 of GRh2-PEG-vpl6 was added into 5 mL of deionized water at 37℃ and then dialyzed in flowing water for 8 h. The particle size, polydispersity（PDI） and Zeta potential were（112.64 ± 4. 28） nm, （0. 224 ± 0. 002）, and （ - 13. 82 ± 2. 74） mV, respectively. GRh2-PEG-vpl6 micelles were potentially stable in various environments, such as stimulation at pH 4. 5 - 7.4, dilution with 50 equivalent volume of water and co-incubation with fetal bovine serum （ FBS）. The 48 hour-accumulative release rate of ginsenoside Rh2 and etoposide at pH 6.5 were 42.5% and 52.5% ,respectively. Conclusion：GRh2-PEG-vpl6 micelles carrying both western and traditional Chinese medicines can be used as a promising nano-sized drug delivery system.

关 键 词：中西药联用 两亲性胶束 体外释放 人参皂苷RH2 依托泊苷 

分 类 号：R943.42[医药卫生—药剂学] R979.1[医药卫生—药学]