摘要目的 研究包载改构型酸性成纤维细胞生长因子1(NMFGF1)的聚乙二醇(PEG)化长循环脂质体结合超声靶向微泡爆破技术(UTMD)对糖尿病心肌病(DCM)的治疗效果及机制.方法 新型水包水型乳化法制备载药长循环脂质体,并进行质量检测.选择15只SD大鼠作为正常对照组,其余腹腔注射链脲佐菌素(70 mg/kg)建立糖尿病模型,12周后通过超声心功能检查筛选出DCM大鼠.药物干预2周再饲养2周后行超声检查,评价各组大鼠心功能.处死大鼠取出心肌组织,通过天狼猩红染色、TUNEL凋亡染色检测心肌胶原容积分数(CVF)和心肌细胞凋亡指数(AI).结果 载药纳米脂质体形态圆整,包封率高达90.3％±1.4％.与DCM、DCM NMFGF1和NMFGF1-PEG脂质体组相比,NMFGF1-PEG+UTMD组大鼠的左心室舒张末内径(LVIDd)[(7.36±0.42)对(5.75±0.24)、(6.64±0.27)、(6.72±0.24)mm,均P<0.05]、左心室短轴缩短率(LVFS)[(50±3)对(33±2)、(44±5)、(43±3)mm,均P<0.05]显著升高,而左心室后壁厚度(LVPW)[(1.65±0.07)对(1.89±0.08)、(1.73±0.11)、(1.73±0.07)mm,均P<0.05]显著下降.天狼星红及TUNEL凋亡染色显示,NMFGF1-PEG+UTMD干预组的CVF及凋亡指数显著低于DCM组及其他各药物治疗组(均P<0.05).结论 载药PEG化长循环脂质体结合UTMD技术能够将NMFGF1高效、靶向递送到心肌组织,从而发挥NMFGF1抗氧化应激损伤效果,有望成为治疗DCM的一种新方法.

abstractsObjective To investigate the therapeutic effect and mechanism of non-mitogenic acid fibroblast growth factor 1( NMFGF1) on diabetic cardiomyopathy ( DCM) by using PEG-modified nano-liposomes combined with ultrasound-targeted microbubble destruction technique ( UTMD ) . Methods The NMFGF1 loaded PEG-modified nano-liposomes were prepared by a water-in-water emulsion method and their quality inspections were also investigated. Type 1 diabetes animal model was induced by intraperitoneal injection of streptozotocin ( 70 mg/kg) in male SD rats. The diabetic rats were raised twelve weeks after the diabetes model was established and DCM rats were selected by ultrasonic heart function examination. After two weeks of intervention, all rats were kept for another two weeks and then underwent transthoracic echocardiography examination. The rats were sacrificed and myocardial tissue was obtained to quantify myocardial collagen fraction ( CVF ) and cardiac myocyte apoptotic index by Sirius red staining and TUNEL staining. Results NMFGF1-loaded PEG-nano-liposomes showed a good morphology and 90.3％± 1.4％ NMFGF1 encapsulation efficiency. Compared with DCM group, NMFGF1group, and NMFGF1-PEG-nano-liposomes group, NMFGF1-loaded PEG-nano-liposome plus UTMD group showed increased left ventricular end diastolic diameter (LVIDd) [(7.36±0.42) vs (5.75±0.24), (6.64±0.27), (6.72±0.24)mm, all P<0.05]and leftventricularfractionshortening(LVFS) [(50±3) vs (33±2), (44±5), (43±3)mm, all P<0.05], and decreased left ventricular posterior wall thickness (LVPW) [(1.65±0.07) vs (1.89±0.08), (1.73±0.11), (1.73&nbsp;±0.07) mm, all P<0.05], with decreased CVF and apoptotic index(all P<0.05). Conclusion PEG-nano-liposomes combining with UTMD technique has a greater translational potential in the delivery of NMFGF1 for the treatment of DCM by attenuating oxidative stress-induced injury and may provide a promising strategy for treating diabetes cardiomyopathy.