Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Biomaterials. 2011 Jan;32(2):565-78. doi: 10.1016/j.biomaterials.2010.08.097.
Proper spatio-temporal delivery of multiple therapeutic proteins represents a major challenge in therapy strategies aimed at inducing myocardial regeneration after myocardial infarction (MI). We hypothesized that the dual delivery of insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) by injectable affinity-binding alginate biomaterial would maximize their therapeutic effects, leading to a more favorable course of tissue restoration after acute MI. A sequential release of IGF-1 followed by HGF was attained from affinity-binding alginate biomaterial, which also protected the proteins from proteolysis (shown by mass spectroscopy). The released factors retained bioactivity, as judged by their capability to activate their respective signaling pathways and to prevent cardiomyocyte apoptosis in vitro. In a rat model of acute MI, an intramyocardial injection of the dual IGF-1/HGF affinity-bound alginate biomaterial preserved scar thickness, attenuated infarct expansion and reduced scar fibrosis after 4 weeks, concomitantly with increased angiogenesis and mature blood vessel formation at the infarct. Furthermore, this treatment prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry and increased the incidence of GATA-4-positive cell clusters. The dual delivery of IGF-1 and HGF from affinity-binding alginate biomaterial represents a useful strategy to treat MI. It showed a marked therapeutic efficacy at various tissue levels, as well as potential to induce endogenous regeneration of cardiac muscle.
多种治疗性蛋白的时空递呈在旨在诱导心肌梗死后心肌再生的治疗策略中是一个主要挑战。我们假设通过可注射的亲和结合藻酸盐生物材料双重递呈胰岛素样生长因子-1（IGF-1）和肝细胞生长因子（HGF）将最大限度地提高它们的治疗效果，导致急性心肌梗死后组织修复的更有利过程。亲和结合藻酸盐生物材料实现了 IGF-1 随后是 HGF 的顺序释放，并且还保护了蛋白质免受蛋白水解（通过质谱法证明）。释放的因子保持生物活性，因为它们能够激活各自的信号通路并防止体外心肌细胞凋亡。在急性心肌梗死的大鼠模型中，心肌内注射双重 IGF-1/HGF 亲和结合藻酸盐生物材料在 4 周后保持了疤痕厚度，减轻了梗塞扩张并减少了疤痕纤维化，同时伴随着梗塞处的血管生成和成熟血管形成增加。此外，这种治疗方法还可以防止细胞凋亡，诱导心肌细胞细胞周期再进入并增加 GATA-4 阳性细胞簇的发生率。从亲和结合藻酸盐生物材料双重递呈 IGF-1 和 HGF 是治疗 MI 的一种有效策略。它在各种组织水平上显示出明显的治疗效果，并具有诱导心肌内源性再生的潜力。
