缓释载药聚乳酸凝胶预防气管纤维组织增生

Action of slow-release drug deliver system with poly lactic acid hydrogels in prevention of tracheal fibroplasia

目的探讨丝裂霉素C(mitomycin C,MMC)与地塞米松磷酸钠(dexamethasone sodium phosphate,DSP)的聚乳酸凝胶对气管瘢痕组织形成的抑制作用。方法在体外缓释实验中,将MMC与DSP聚乳酸凝胶后置于恒温水浴摇床中,药物的累积浓度通过紫外分光光度法测定。在体内缓释试验中,通过喉气管外壁损伤建立瘢痕形成的动物模型。将42只新西兰大白兔进行气管外壁刮伤后分成7组:实验组包括载MMC组3组(0.1、0.2、0.4 mg)、载DSP组3组(1、2、3 mg)和空白对照组1组。0.4 mg MMC组动物于术后不同时间抽血,通过质谱测量体内药物浓度及血常规。术后4周处死动物,取气管外壁标本,HE染色观察纤维组织增生厚度。结果体外实验1 mg MMC、2 mgDSP凝胶缓释分别可达35 d及28 d以上。动物体内两种药物凝胶在术后4周未完全降解。两种药物剂量组(除0.1 mgMMC组外)与对照组比较,对气管壁纤维组织增生有明显抑制作用;在MMC各剂量组中,0.4 mg MMC组比其他组对纤维组织增生的抑制程度更明显;在DSP不同剂量组中,抑制作用无统计学意义;0.4 mg MMC与3种剂量的DSP组纤维组织增生厚度差异均无统计学意义。术后1、7、14 d白细胞计数无统计学差异。结论 MMC及DSP聚乳酸凝胶在动物体内外释放时间均长达4周,可作为预防瘢痕形成的缓释用药。本研究为未来研制聚乳酸聚乙醇酸支架涂层药物缓释载体对喉气管狭窄的治疗提供了实验基础。

OBJECTIVE To compare the effect of slow-release mitomycin C（MMC）and dexamethasone sodium phosphate（DSP） with polylactic acid（PLA）hydrogels on prevention of tracheal fibroplasia.METHODS In vitro slow-release study,MMC and DSP mixed with PLA hydrogels was palced in the water bath oscillators,the cumulative concentrations of MMC and DSP were determined by ultraviolet spectrophotometry.In vivo study,the rabbit model of tracheal fibroplasia was made through scratching the tracheal wall.After scuffing the tracheal walls,forty-two rabbits were divided into 7 groups averagely,three MMC groups（0.1、0.2、 0.4 mg）,three DSP groups（1、2、3 mg）and one control group.And then the blood drug level of rabbits in 0.4 mg MMC group at different time after operation was determined by mass spectrometry（MS）.The blood routine test was done at above-mentioned corresponding time.Four weeks after operation,each animal was killed to get tracheal walls,which were then stained with hematoxylin and eosin（HE）,and the thickness of tracheal fibroplasia was calculated.RESULTS In vitro study,PLA hydrogels with 1 mg MMC and 2 mg DSP could release drug over 35 days and 28 days respectively.And in vivo study,these two kinds of PLA hydrogels hadn＇t degraded completely after 4 weeks.The tracheal wall fibroplasia in control group was thicker than that in both DSP and MMC groups except 0.1 mg MMC group.Among MMC groups,0.4 mg MMC group had the best effect in inhibiting fibroplasia.While in DSP groups,the thickness of fibroplasia had no difference among three groups;and the difference of fibroplasia thickness was not significant between DSP groups and 0.4 mg MMC group.The leukocyte count on the 1st day,7th day and 14th day after operation had no significant difference.CONCLUSION MMC and DSP PLA hydrogels could release drug over 4 weeks either in vitro or in vivo.Both MMC/PLA and DSP/PLA hydrogels could inhibit fibroplasia of the tracheal wall and be used as slow-release administration in prevention of fibroplasia,which provided experimental basis for studying PLGA scaffold slow-delivery system for treating laryngotracheal stenosis in the future.