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Injectable Polymeric Delivery System for Spatiotemporal and Sequential Release of Therapeutic Proteins To Promote Therapeutic Angiogenesis and Reduce Inflammation
ACS Biomaterials Science & Engineering ( IF 5.8 ) Pub Date : 2020-01-24 , DOI: 10.1021/acsbiomaterials.9b01758
Adam J. Rocker 1 , David J. Lee 1 , Robin Shandas 1 , Daewon Park 1
Affiliation  

Myocardial infarction (MI) causes cardiac cell death, induces persistent inflammatory responses, and generates harmful pathological remodeling, which leads to heart failure. Biomedical approaches to restore blood supply to ischemic myocardium, via controlled delivery of angiogenic and immunoregulatory proteins, may present an efficient treatment option for coronary artery disease (CAD). Vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation, while platelet-derived growth factor (PDGF) is needed later to recruit pericytes, which stabilizes new vessels. Anti-inflammatory cytokines like interleukin-10 (IL-10) can help optimize cardiac repair and limit the damaging effects of inflammation following MI. To meet these angiogenic and anti-inflammatory needs, an injectable polymeric delivery system composed of encapsulating micelle nanoparticles embedded in a sulfonated reverse thermal gel was developed. The sulfonate groups on the thermal gel electrostatically bind to VEGF and IL-10, and their specific binding affinities control their release rates, while PDGF-loaded micelles are embedded in the gel to provide the sequential release of the growth factors. An in vitro release study was performed, which demonstrated the sequential release capabilities of the delivery system. The ability of the delivery system to induce new blood vessel formation was analyzed in vivo using a subcutaneous injection mouse model. Histological assessment was used to quantify blood vessel formation and an inflammatory response, which showed that the polymeric delivery system significantly increased functional and mature vessel formation while reducing inflammation. Overall, the results demonstrate the effective delivery of therapeutic proteins to promote angiogenesis and limit inflammatory responses.

中文翻译:

时空性和顺序性释放治疗性蛋白质的可注射聚合物递送系统,以促进治疗性血管生成和减少炎症

心肌梗塞(MI)会导致心肌细胞死亡,引起持续的炎症反应,并产生有害的病理重塑,从而导致心力衰竭。通过控制血管生成和免疫调节蛋白的递送来恢复缺血心肌的血液供应的生物医学方法,可能为冠状动脉疾病(CAD)提供一种有效的治疗选择。血管内皮生长因子(VEGF)是启动新血管形成所必需的,而血小板衍生的生长因子(PDGF)则在以后需要募集周细胞来稳定新血管。诸如白细胞介素10(IL-10)之类的抗炎细胞因子可以帮助优化心脏修复并限制MI后炎症的破坏作用。为了满足这些血管生成和抗炎的需求,开发了一种可注射的聚合物递送系统,该系统由包埋在磺化反向热凝胶中的胶束纳米颗粒组成。热凝胶上的磺酸根基团与VEGF和IL-10静电结合,它们的特异性结合亲和力控制它们的释放速率,而PDGF加载的胶束被嵌入凝胶中以提供生长因子的顺序释放。进行了体外释放研究,证明了递送系统的顺序释放能力。使用皮下注射小鼠模型体内分析了递送系统诱导新血管形成的能力。组织学评估用于量化血管形成和炎症反应,这表明聚合物递送系统显着增加了功能性血管和成熟血管的形成,同时减少了炎症。总体而言,结果证明了治疗性蛋白质的有效传递可促进血管生成并限制炎症反应。
更新日期:2020-01-24
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