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目的:制备一种超声和p H双重响应的同时载有阿霉素(DOX)与石胆酸(LA)的纳米胶束,实现两种药物的共转运。方法:将叠氮化的石胆酸(LA-(N3)_2)与两个丙炔胺化β-环糊精(β-CD-C≡CH)通过点击反应结合,得到一种两亲性β-环糊精二聚体(LA-(CD)_2)。该环糊精二聚体在水溶液中发生自组装,同时包裹疏水性药物阿霉素,最终得到阿霉素与石胆酸共转运的纳米胶束(LA-CD2/DOX)。通过核磁共振光谱和飞行时间质谱表征LA-(CD)2的结构,透射电镜(TEM)和动态光散射(DLS)表征共转运纳米粒的形貌和大小,动态透析法模拟体外释药,监测在不同p H值和超声作用下纳米胶束的释药特性,同时采用人口腔表皮样癌细胞(KB细胞)测定LA-(CD)2/DOX的细胞毒性。结果:1经核磁共振和飞行时间质谱表征LA-(CD)2成功合成。2透射电镜和动态光散射证实LA-(CD)2自组装成形态规整的纳米胶束,Dz=128 nm,PDI=0.21。3体外释药实验结果表明DOX的释药具有p H和超声双重响应性,而LA的释药只具有p H响应性。4细胞实验证实LA-CD2/DOX的细胞毒性高于DOX和LA。结论:LA-(CD)2/DOX可有望成为一种p H和超声双重响应的抗肿瘤药物共转运纳米载体。
OBJECTIVE: To prepare a nanomicelle containing doxorubicin (DOX) and lithocholic acid (LA) with double response of ultrasound and p H to achieve co-transport of two drugs. Methods: Azide lithocholic acid (LA- (N3) _2) was coupled with two propylamidated β-cyclodextrins (β-CD-C≡CH) by click reaction to obtain an amphipathic β-cyclodextrin dimer (LA- (CD) _2). The cyclodextrin dimer self-assembled in aqueous solution, at the same time wrapped hydrophobic drug doxorubicin, and finally doxorubicin co-transport with lithocholic acid micelles (LA-CD2 / DOX). The morphology and size of co-transfected nanoparticles were characterized by nuclear magnetic resonance spectroscopy and time-of-flight mass spectrometry. The structure and morphology of LA- (CD) 2 were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) The drug release characteristics of nanomicelles under different p H values and ultrasound were measured, and the cytotoxicity of LA- (CD) 2 / DOX was measured simultaneously using human oral epidermoid carcinoma cells (KB cells). RESULTS: 1 LA- (CD) 2 was successfully synthesized by nuclear magnetic resonance and time-of-flight mass spectrometry. 2 TEM and dynamic light scattering confirmed the self-assembly of LA- (CD) 2 into a structured nanomicelles with Dz = 128 nm and PDI = 0.21.3. The in vitro drug release results showed that the drug release of DOX was both p H and ultrasound Responsiveness, whereas release of LA only had p H responsiveness. 4 cell experiments confirmed that LA-CD2 / DOX cytotoxicity higher than DOX and LA. Conclusions: LA- (CD) 2 / DOX is expected to be a pH and ultrasound dual-response antitumor drug co-delivery nanocarrier.