Wenzhou Medical University, Wenzhou, Zhejiang Province 325035, China.
Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
J Control Release. 2014 Jul 28;186:22-31. doi: 10.1016/j.jconrel.2014.04.054. Epub 2014 May 9.
Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality among the diabetic patients and currently there is no effective means to reverse its pathological progress. Basic fibroblast growth factor (bFGF) has shown promise as a molecular therapy for DCM, but its delivery is inefficient and non-specific. In the present study, a therapy combining nanoparticle (NP) carrier and ultrasound-targeted microbubble destruction (UTMD) was reported the first time for bFGF delivery to the heart of diabetic rats. bFGF-loaded NP (bFGF-NP) were prepared with Poloxamer 188-grafted heparin copolymer using water-in-water technique, and the morphology, encapsulation efficiency, and bioactivity of bFGF-NP were studied. The cellular uptake and cytotoxicity of bFGF-NP were evaluated with primary cultures of the left ventricular (LV) cardiomyocytes in vitro. Therapeutic effects of bFGF-NP/UTMD on the heart of DCM rats were studied by measuring LV systolic and diastolic functions, hemodynamic characteristics and indicators of cardiac remodeling including myocardial collagen volume fraction and capillary density. Results demonstrated that bFGF-NP showed good round morphology, efficient bFGF encapsulation and stable bioactivity of bFGF in vitro. bFGF-NP/UTMD combined treatment significantly enhanced the efficiency of bFGF cellular uptake (P<0.05) without obvious cytotoxicity. Significant improvements (P<0.05) in both cardiac functions and tissue morphology in the DCM rats were observed in bFGF-NP/UTMD group. These were not achievable using free bFGF, bFGF-NP or UTMD treatment alone. Our results show that combining a non-viral vector with UTMD technique is an effective strategy to deliver bFGF to the heart, and the resulting growth factor therapy has demonstrated potential to reverse the progress of DCM by restoring the cardiac functions and even the structure of damaged cardiac tissues.
糖尿病心肌病（DCM）是糖尿病患者发病率和死亡率的主要原因，目前尚无有效的方法来逆转其病理进展。碱性成纤维细胞生长因子（bFGF）已被证明是治疗 DCM 的一种有前途的分子疗法，但它的传递效率低且非特异性。在本研究中，首次报道了一种将纳米颗粒（NP）载体和超声靶向微泡破坏（UTMD）相结合的治疗方法，用于将 bFGF 递送到糖尿病大鼠的心脏。使用水包水技术，用接枝有泊洛沙姆 188 的肝素共聚物制备 bFGF 负载的 NP（bFGF-NP），并研究了 bFGF-NP 的形态、包封效率和生物活性。通过体外原代培养左心室（LV）心肌细胞评估 bFGF-NP 的细胞摄取和细胞毒性。通过测量 LV 收缩和舒张功能、血流动力学特征以及包括心肌胶原容积分数和毛细血管密度在内的心脏重构指标，研究了 bFGF-NP/UTMD 对 DCM 大鼠心脏的治疗效果。结果表明，bFGF-NP 具有良好的圆形形态、高效的 bFGF 包封和稳定的 bFGF 生物活性。bFGF-NP/UTMD 联合治疗显著增强了 bFGF 的细胞摄取效率（P<0.05），且无明显细胞毒性。bFGF-NP/UTMD 组 DCM 大鼠的心脏功能和组织形态均得到显著改善（P<0.05）。单独使用游离 bFGF、bFGF-NP 或 UTMD 治疗均无法实现这些效果。我们的结果表明，将非病毒载体与 UTMD 技术相结合是将 bFGF 递送到心脏的有效策略，并且这种生长因子治疗通过恢复心脏功能甚至受损心脏组织的结构，显示出逆转 DCM 进展的潜力。
