包载吲哚菁绿和阿霉素胶束的制备与体外抗肿瘤效果评价  

Preparation of indocyanine green and doxorubicin micelles and evaluation of its anti-tumor effect in vitro

作　　者：张米娅 陈亮 庞海燕 杨红[1] ZHANG Mi-ya;CHEN Liang;PANG Hai-yan;YANG Hong(College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China)

机构地区：[1]苏州大学药学院,苏州215123

出　　处：《中国新药杂志》2021年第13期1220-1226,共7页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81473166)。

摘　　要：目的:本研究旨在联合光治疗和化疗作用,制备共包载吲哚菁绿(ICG)和阿霉素(DOX)的胶束(ID-M),对制备得到的胶束进行表征并在细胞水平考察其体外抗肿瘤效果。方法:采用超声透析法制备ID-M,制备单包载ICG的胶束(I-M)和单包载DOX的胶束(D-M)作为对照。对胶束的粒径、Zeta电位、包封率及释放行为等进行测定,并通过ID-M对4T1细胞的作用,考察其抗肿瘤效果和作用机制。结果:制得的ID-M平均水合粒径为80.4 nm且带负电,多分散系数为0.252(<0.3),ICG和DOX的包封率分别为92.5%和96.8%;ID-M的升温实验结果达到(36.5±1.1)℃。体外释放实验表明ID-M具有明显的缓释效果。细胞实验证明:4T1细胞对ID-M的摄取量较游离药物均提升了近2倍量。ID-M在光照后抑制4T1细胞生长的IC50为0.72μg·mL-1,较游离ICG/DOX下降了3.6倍。光照前ID-M中的DOX主要定位在溶酶体中,光照后ID-M中的ICG使细胞内的ROS水平提高,溶酶体膜破坏,DOX进入细胞核中发挥化疗作用。结论:本研究成功制备了ID-M,有效结合光治疗和化疗发挥协同抗肿瘤作用。Objective:To combine the chemotherapy and photodynamic therapy in one system,the micelles(ID-M)that co-loaded the photosensitizer indocyanine green(ICG)and the chemotherapeutic drug doxorubicin(DOX)were prepared and characterized.The anti-tumor effects of ID-M in vitro were further investigated.Methods:An ultrasound dialysis method was used to prepare the micelles containing ICG and DOX(ID-M),while the singleencapsulated ICG micelles(I-M)and the single-encapsulated DOX micelles(D-M)were prepared using the same method as the controls.The particle size,Zeta potential,encapsulation efficiency and drug release behaviors of the micelles were measured.In addition,the anti-tumor effects and mechanism of ID-M in 4T1 cells were investigated.Results:The average hydrated diameter of ID-M particles was 80.4 nm with negative charge,and the coefficient of the particle size dispersion was 0.252(<0.3).The encapsulation efficiency of ICG and DOX in ID-M were 92.5%and 96.8%,respectively.The results of the temperature warming testing under irradiation of ID-M solution reached(36.5±1.1)℃.The release experiment of ID-M in vitro showed a significant sustained-release effect.Cell experiment proved that the uptake of 4T1 cells for ID-M was nearly 2 times higher than that for free drugs.The IC50 of ID-M inhibiting the growth of 4T1 cells with irradiation was 0.72μg·mL-1,which was 3.6-fold lower than that of free ICG/DOX.Before light exposure,ID-M was mainly located in the lysosome.However,after light exposure,the ROS levels in the cells were increased due to the existence of ICG in ID-M,which damaged the lysosomal membrane and made DOX in ID-M enter to the nucleus to play a chemotherapeutic effect.Conclusion:In this study,the micelles(ID-M)with synergistic antitumor effects of phototherapy and chemotherapy were successfully prepared.

关 键 词：阿霉素 吲哚菁绿 胶束 光治疗-化疗 协同抗肿瘤作用 

分 类 号：R943[医药卫生—药剂学] R965[医药卫生—药学]