雷帕霉素聚乳酸-聚乙醇酸纳米粒子的制备、表征及血管内局部给药效能  

Rapamycin-loaded Poly(lactic-co-glycolic) Acid Nanoparticles for Intraarterial Local Drug Delivery:Preparation,Characterization,and in vitro/in vivo Release

作　　者：苗立夫 杨菁[2] 黄超联 宋存先[2] 曾玉杰[3] 陈连凤[4] 朱文玲[4] 

机构地区：[1]清华大学第一附属医院心脏中心,北京100016 [2]中国医学科学院北京协和医学院生物医学工程研究所天津市生物材料重点实验室,天津300192 [3]中日友好医院心内科,北京100029 [4]中国医学科学院北京协和医学院北京协和医院心脏内科,北京100730

出　　处：《中国医学科学院学报》2008年第4期491-497,共7页Acta Academiae Medicinae Sinicae

基　　金：国家自然科学基金(30240021);清华-裕元医学科学研究基金(20240000556)~~

摘　　要：目的制备包载雷帕霉素(RPM)的聚乳酸-聚乙醇酸共聚物(PLGA)纳米粒子(NPs),评估其通过DISPATCHTM球囊在血管内局部给药的应用条件及给药效能。方法超声乳化-溶剂挥发法制备RPM-PLGA-NPs,测定其载药量和包封率。激光光散射实验测定纳米粒子的粒径及分布,扫描电镜观察纳米粒子的表面形态。双室扩散池行体外药物释放实验,计算释放量,绘制累积释放曲线。通过新西兰白兔腹主动脉及小型猪冠状动脉内局部给药模型评估DISPATCHTM球囊血管内应用RPM-PLGA-NPs的实验条件及给药后不同时段血管组织药物浓度。结果成功制备了平均粒径为246.8 nm的RPM-PLGA-NPs,包封率为77.53%,平均载药量为19.42%。体外释放近似于零级过程,至2周释放75%的药物。成功建立经DISPATCHTM球囊新西兰白兔腹主动脉、中国实验用小型猪冠状动脉内局部给药模型,20.27 kPa灌注压力下经DISPATCHTM导管球囊灌注5 mg/ml RPM-PLGA-NPs 10 min,第7和14天后局部组织药物浓度为(2.438±0.439)和(0.529±0.144)μg/mg干重。结论超声乳化-溶剂挥发法制备RPM-PLGA-NPs方法稳定可靠,包封效率高,载药量控制稳定,粒径小、范围窄,体外释放药物恒定、效果满意。纳米载药系统结合DISPATCHTM球囊导管能显著延长局部血管内药物浓度,为血管疾病提供新的治疗手段。Objective To sought to engineer and characterize a biodegradable nanoparticles（NPs）containing rapamycin which use poly（lactic-co-glycolic） acid（PLGA） as the carrier matrix and to assess its in vivo release characteristics by local drug delivery system intravascularly.Methods Rapamycin-loaded PLGA NPs were prepared by an emulsification/solvent evaporation technique,and NPs size distribution was assessed by submicro laser defractometer.The particle morphology was observed by scanning electron microscopy.In vitro release from the NPs was performed in TE buffer at 37℃ under rotation utilizing double-chamber diffusion cells on a shake stander.In vivo NPs intravascular local delivery were performed by DISPATCH^TM catheter in New Zealand rabbit abdominal aorta and Chinese experimental mini-pigs coronary artery models.Results Biodegradable rapamycin loaded PLGA NPs were constructed successfully by emulsification solvent-evaporation technique.The diameter of rapamycin-PLGA NPs was around 246.8 nm with very narrow size distribution,and rapamycin-NPs showed good spherical shape with smooth uniform surface.Rapamycin loaded in NPs were around was 19.42%.Encapsulation efficiency of drug was over 77.53%.The in vitro release of rapamycin from NPs showed that 75% of the drug was sustained released over 2 weeks and controlled release in a linear pattern.After a single 10 minutes infusion of rapamycin-PLGA NPs suspension（5 mg/ml）under 20.27 kPa through DISPATCH^TM catherter in vivo,the mean rapamycin levels at 7 day and 14 day were（2.438±0.439） and（0.529±0.144）μg/mg of the dry-weight of the artery segments（2 cm） which local delivery were administrated.Conclusions PLGA NPs controlled drug delivery system for intraarterial local anti-proliferative drug delivery can potentially improve local drug concentration and prolong drug residence time in animal model in vivo.It should be appropriate for further study of its therapy efficiency in human.

关 键 词：雷帕霉素 聚乳酸-聚乙醇酸共聚物 纳米粒子 局部给药 

分 类 号：R318.08[医药卫生—生物医学工程] R972.6[医药卫生—基础医学]