摘要
利用中药活性成分人参皂苷Rg_(3)完全代替胆固醇作为脂质体膜材料,制备同时负载双氢青蒿素与紫杉醇的人参皂苷Rg_(3)脂质体,并评价其对三阴性乳腺癌的体外抗肿瘤作用。采用薄膜水化法制备脂质体,单因素试验优化脂质体处方工艺,对其粒径、Zeta电位和稳定性等理化性质表征,评价药物在多种介质(pH 5.0、7.4)中的释放行为。以CCK-8方法检测其对MDA-MB-231细胞和4T1细胞的增殖抑制作用。以细胞划痕实验评价其对MDA-MB-231细胞和4T1细胞迁移能力的影响,并进一步评价脂质体的靶向能力和溶酶体逃逸机制。利用H9c2细胞对制剂潜在的心肌毒性进行安全性评价。所制备的脂质体呈类球状、粒径均匀分布,平均粒径为(107.81±0.01)nm,Zeta电位为(-2.78±0.66)mV,双氢青蒿素和紫杉醇的包封率分别为57.76%±1.38%和99.66%±0.07%,总载药量为4.46%±0.71%,双氢青蒿素和紫杉醇的累积释放度在pH 5.0条件下优于pH 7.4,低温下储存7 d稳定性良好。给药24 h后,当双氢青蒿素的浓度为70μmol·L^(-1)时,负载双氢青蒿素与紫杉醇的人参皂苷Rg_(3)脂质体对MDA-MB-231细胞和4T1细胞的增殖抑制率显著高于阳性药阿霉素和游离药物(P<0.01)。与游离药物相比,脂质体能显著抑制MDA-MB-231细胞和4T1细胞的迁移(P<0.05)。脂质体具备主动靶向性和较好的“溶酶体逃逸”功能。特别是,相比于游离药物,脂质体对心肌细胞毒性明显降低(P<0.05),证明制剂具有降低心肌毒性的潜力。该研究证明了人参皂苷Rg_(3)作为脂质体药物处方中脂类的良好替代品的“药辅合一”特性,进一步推动治疗肿瘤的中药创新药物发展。
Ginsenoside Rg_3,an active component of traditional Chinese medicine(TCM),was used as the substitute for cholesterol as the membrane material to prepare the ginsenoside Rg_3-based liposomes loaded with dihydroartemisinin and paclitaxel.The effect of the prepared drug-loading liposomes on triple-negative breast cancer in vitro was evaluated.Liposomes were prepared with the thin film hydration method,and the preparation process was optimized by single factor experiments.The physicochemical properties(e.g.,particle size,Zeta potential,and stability) of the liposomes were characterized.The release behaviors of drugs in different media(pH 5.0 and pH 7.4) were evaluated.The antitumor activities of the liposomes were determined by CCK-8 on MDA-MB-231 and 4T1 cells.The cell scratch test was carried out to evaluate the effect of the liposomes on the migration of MDA-MB-231 and 4T1 cells.Further,the targeting ability of liposomes and the mechanism of lysosome escape were investigated.Finally,H9c2 cells were used to evaluate the potential cardiotoxicity of the preparation.The liposomes prepared were spheroid,with uniform particle size distribution,the ave-rage particle size of(107.81±0.01) nm,and the Zeta potential of(2.78±0.66) mV.The encapsulation efficiency of dihydroartemisinin and paclitaxel was 57.76%±1.38% and 99.66%±0.07%,respectively,and the total drug loading was 4.46%±0.71%.The accumulated release of dihydroartemisinin and paclitaxel from the liposomes at pH 5.0 was better than that at pH 7.4,and the liposomes could be stored at low temperature for seven days with good stability.Twenty-four hours after administration,the inhibition rates of the ginsenoside Rg_3-based liposomes loaded with dihydroartemisinin(70 μmol·L^(-1)) and paclitaxel on MDA-MB-231 and 4T1 cells were higher than those of the positive control(adriamycin) and free drugs(P<0.01).Compared with free drugs,liposomes inhibited the migration of MDA-MB-231 and 4T1 cells(P<0.05).Liposomes demonstrated active targeting and lysosome escape.In parti
作者
刘花
刘艺
李娜
张国琴
王萌
LIU Hua;LIU Yi;LI Na;ZHANG Guo-qin;WANG Meng(State Key Laboratory of Component-based Chinese Medicine,Research Institute of Traditional Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;School of Traditional Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China)
出处
《中国中药杂志》
CAS
CSCD
北大核心
2023年第13期3472-3484,共13页
China Journal of Chinese Materia Medica
基金
天津市研究生科研创新项目(2021YJSB284)
天津中医药大学研究生科研创新项目(YJSKC-20211016)
天津市教委科研重点项目(2021ZD009)
国家自然科学基金面上项目(81873191)。
