目的: 研究离子交换型载阿霉素聚丙烯酸栓塞微球的制备方法与性质评价。方法: 采用反相悬浮聚合法制备空白聚丙烯酸栓塞微球[poly (acrylic acid) microspheres,PMs],通过离子交换原理将阿霉素载入该微球,制备载阿霉素的聚丙烯酸栓塞微球[doxorubicin-loaded poly (acrylic acid) microspheres,DPMs]。采用光学显微镜考察两种微球的形态和粒径分布,荧光显微镜和激光扫描共聚焦显微镜考察载药微球中阿霉素的分布,物性测定仪测定PMs和DPMs的弹性,HPLC法测定PMs的载药性质和DPMs的释药性质。以0.1 mL的DPMs栓塞家兔肝动脉评价其在动物体内的栓塞效果。结果: 制备的PMs和DPMs形态圆整、表面光滑,能够均匀分散,阿霉素主要分布在靠近微球表面的区域且分布均匀。PMs和DPMs的平均粒径分别为(283±136) μm和(248±149) μm,杨氏模量分别为(62.63±1.65) kPa和(93.94±1.10) kPa,空白和载药微球均具有良好的抗压缩能力。PMs在12 h时达到载药平衡,包封率大于99%,在浓度为5.0 g/L和12.5 g/L的阿霉素溶液中微球的载药量分别为(19.78±0.27) g/L和(49.45±0.37) g/L;DPMs在磷酸盐缓冲液(phosphate buffered saline,PBS)中缓慢释放阿霉素,载药量为(19.78±0.27) g/L和(49.45±0.37) g/L的微球24 h体外累积释放百分数分别为6.82%±0.02%和2.83%±0.10%。影像学结果显示,DPMs成功地栓塞了家兔的肝动脉。结论: 聚丙烯酸微球具有良好的载阿霉素性能,DPMs是一种潜在的可用于动脉化疗栓塞的新型药物递送系统。

Objective: To prepare ion exchange doxorubicin-loaded poly (acrylic acid) microspheres (DPMs) and evaluate the properties of these chemoembolic agents.Methods:Poly (acrylic acid) microspheres (PMs) without drug were prepared by inverse suspension polymerization method and then doxorubicin was loaded by ion exchange mechanism to prepare DPMs. Optical microscope was used to investigate the morphology and particle size distribution of PMs and DPMs; fluorescence microscope and confocal microscope were used to observe the distribution of doxorubicin after drug loading. Elasticities of both the microspheres were evaluated by texture analyzer. High performance liquid chromatography (HPLC) method was established to determine the drug loading behavior of PMs and releasing behavior of DPMs. The in vivo embolic property was evaluated by embolizing the hepatic artery of a rabbit with 0.1 mL of DPMs.Results:PMs and DPMs were both spherical in shape, smooth in surface and dispersed well. Doxorubicin was mainly in the outer area inside of DPMs and distributed evenly. The average particle size of PMs and DPMs were (283±136) μm and (248±149) μm, respectively. PMs and DPMs both had good compression ability with the Young’s modulus of (62.63±1.65) kPa and (93.94±1.10) kPa separately. PMs reached the drug loading balance at 12 h, and the entrapment efficiency was greater than 99%. Drug loading of PMs in doxorubicin solution at the concentration of 5.0 g/L and 12.5 g/L was (19.78±0.27) g/L and (49.45±0.37) g/L, respectively. Doxorubicin released slowly from DPMs in PBS and the accumulative release percentages of DPMs with corresponding drug loading were 6.82%±0.02% and 2.83%±0.10% after 24 h, respectively. Arterial angiograms showed that the hepatic artery of the rabbit was successfully embolized with DPMs.Conclusion:DPMs with good performance of loading doxorubicin could be a potential embolic agent for transcatheter arterial chemoembolization.