表面修饰紫杉醇纳米粒局部给药抑制血管再狭窄的研究  

Surface-modified paclitaxel-loaded nanoparticles as local delivery system for the prevention of vessel restenosis

作　　者：梅林[1] 宋存先[1] 金旭[1] 车永哲[2] 金喆[3] 孙洪范[1] 

机构地区：[1]中国医学科学院,中国协和医科大学生物医学工程研究所天津市生物医学材料重点实验室,天津300192 [2]南开大学医学院,天津300192 [3]天津市第一中心医院心内科,天津300192

出　　处：《药学学报》2007年第1期81-86,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(50473059);天津市自然科学基金资助项目(023801311).

摘　　要：制备表面修饰紫杉醇纳米粒并观察其抑制兔颈动脉损伤模型新生内膜增生的效果。采用超声乳化-溶剂挥发法制备载紫杉醇纳米粒,用物理吸附法对纳米粒进行表面修饰。对纳米粒进行表征,包封率和体外释放使用高效液相色谱仪进行分析。建立兔颈动脉损伤模型,在血管局部灌注不同浓度的修饰纳米粒。28天后,取出局部给药的颈动脉血管,进行苏木素-伊红(Hematoxylin&Eosinstaining,HE)染色和弹力纤维染色。制备的载紫杉醇纳米粒粒径300nm左右、包封率80%以上且表面带正电荷。体外药物释放呈两相释放。28天后,血管内局部灌注紫杉醇纳米粒悬液可有效抑制血管内皮增生,并呈剂量依赖性。浓度达到30mg.mL-1时,可完全抑制血管内膜增生。血管内局部灌注正电荷修饰的紫杉醇纳米粒悬液可有效抑制血管内皮增生,抑制效果随纳米粒悬液浓度的增加而提高。The novel paclitaxel-loaded nanopaticle through surface modification with didodecylmethylammonium bromide （DMAB） was prepared and its prevenative against neointimal formation in a rabbit carotid artery injury model was tested. Paclitaxel-loaded nanoparticles were prepared from oil-water emulsions using biodegradable poly （lactic acid-co-glycolic acid） （PLGA）. Specific additive for surface conjugation was added after particle formation. To enhance arterial retention using a cationic surfactant, DMAB, was used. The size and distribution, surface morphology and surface charge of the paclitaxel-loaded nanoparticles were then investigated by laser light scattering, scanning electron microscope and zeta potential analyzer. The drug encapsulation efficiency （EE） and in vitro release profile were measured by high-performance liquid chromatography （HPLC）. Balloon injured rabbit carotid arteries were treated with single infusion of the paclitaxel-loaded NP suspension and observed for 28 days. The inhibitory effects of vascular smooth muscle cell migration and proliferation were evaluated as endpoint. The NPs showed spherical shape with diameter ranging from 200 to 500 nm. The negatively charged PLGA NPs shifted to positive after the DMAB modification. The in vitro drug release profile showed a triphasic release pattern. 28 days later, morphologic analysis revealed that the inhibitory effect of intima proliferation is dose-dependent, and the 30 mg · mL^-1 nanoparticle concentration suspension could completely inhibit proliferation of intima. Paclitaxel-loaded nanoparticles through surface modification with DMAB provide an effective means of inhibiting proliferation response to vascular injury in the rabbit.

关 键 词：紫杉醇 纳米粒 溴化双十二烷基二甲基铵 介入治疗 血管再狭窄 

分 类 号：R943[医药卫生—药剂学]