乳酸羟基乙酸共聚物微泡声学造影剂的制备与评估实验研究

Preparation of poly lactic-co-glycolic acid microbubble ultrasonic contrast agent and its evaluation

目的制备乳酸羟基乙酸共聚物(polylactic-co-glycolicacid,PLGA)微泡声学造影剂,考察其理化及声学特性。方法复乳法制备不同聚乳酸/聚羟基乙酸(PLA/PGA)的微泡,考察其理化特性;体内外显影评价不同剂量、不同机械指数条件下微泡造影剂的声学密度(AD)变化规律。结果 PLGA微泡成品呈白色粉末状,以生理盐水或PBS稀释溶解后为乳白色混悬液,pH为6.5±0.3;光镜显示微泡大小均匀,分散程度好;微泡平均粒径1.2μm;Coulter计数显示0.01g多聚体微泡冻干粉溶于10ml蒸馏水中的浓度为(2～4)×109/ml;4℃与常温干燥储存的PLGA微泡10周后再分散其浓度、粒径、pH值无明显差异;体外显影显示声学密度随微泡浓度的升高而增大,同浓度下声学密度与机械指数(mechanicalindex,MI)呈直线相关关系;兔心脏造影检查可观察到PLGA微泡造影剂能顺利通过肺循环实现左心显影,当MI为0.2时,左室内声学密度值较其他3组(MI为0.6、1.0、1.2)均有非常显著性差异。结论 PLGA微泡造影剂具有较高的可控性和稳定性,微泡共振频率较高,可以顺利通过肺循环实现左心室显影。

Objective To prepare the poly lactic-co-glycolic acid（PLGA） microbubble ultrasonic contrast agent and evaluate its physicochemical and acoustic properties.Methods Different PLA/LGA microbubble ultrasonic contrast agents were prepared with the double emulsion method.Their physicochemical properties and acoustic signal intensity change were evaluated in vitro using different doses and mechanical index（MI） of PLGA microbubble ultrasonic contrast agent.Results A cream white suspension was obtained by dissolving the white PLGA microbubble powders in saline or PBS with a pH value of 6.5 ±0.3.Light microscopy showed that the microbubbles were uniform in size and well dispersed.The average diameter of microbubbles was 1.2 μm.Coulter count showed that the concentration of 0.01 g polymicrobubble dry powders dissolved in 10 ml distilled water was 2.0 × 109 /ml-4.0 × 109 /ml.No significant difference was observed in concentration,diameter and pH value in 10 weeks after the PLGA microbubbles were kept at 4℃ or at common temperature.In vitro study showed that the acoustic intensity of PLGA microbubbles increased with their concentration,and was linearly correlated with their mechanical index（MI）.Rabbit cardioroentgenography showed that PLGA microbubbles passed through the pulmonary circulation and achieved the left ventricular imaging in vivo.A significant difference was found in left ventricle acoustic intensity when the MI value was 0.2 compared with when it was 0.6,1.0,and 1.2.Conclusion PLGA microbubble ultrasonic contrast agent has a rather good controllability and stability with a higher resonance frequency,thus being able to pass through the pulmonary circulation and achieve left ventricular imaging.