MMP Responsive Nanoparticles for Treating Acute Myocardial Infarction

摘要 尽管最近取得了进展，但心力衰竭(HF)仍然是美国人的主要死亡原因，其他 西方世界的。大约37%的心肌梗死(MI)患者将在1年内死于心衰， 而那些幸存下来的人中，三分之二没有完全康复。据估计，每年约有55万 美国人将有新的心肌梗死，~20万人将有反复的心肌梗死，导致大量患者遭受 从HF来的。因此，我们的长期目标是开发新的、微创的、有针对性的生物材料 治疗急性心肌梗死(AMI)的基础疗法，从而限制进展为 高频。最近，在开发可注射生物材料方面取得了重大进展，这种材料可以刺激 内源性修复自己或通过控制释放额外的治疗药物。这种方法是 由于潜在的治疗方法可以通过导管以最小的侵入性提供，因此很有吸引力，将是现成的 和成本效益，在治疗性交付的情况下，将提供靶向交付，限制全身非- 针对困扰传统药物的靶向效应。然而，直接注射这些药物的方法 生物材料(无论是通过微创手术还是经皮心内膜注射)是不可能的 由于注射程序存在严重的安全问题，因此将翻译给急性心肌梗死患者，从而 心肌梗死后立即错过了关键的治疗窗口。在一起，私人侦探开发了一种新的 基于生物材料的方法提供治疗，将不需要直接注射到 心脏，这可以实现冠状动脉内输液，这是一种在心肌梗死时可能进行的程序，甚至更少 侵入性静脉(IV)注射。这种方法包括使用酶反应性多肽聚合物。 两亲性纳米颗粒，对基质金属蛋白酶(基质金属蛋白酶-2和基质金属蛋白酶-9)有反应 心肌梗死后心脏升压。纳米粒子经历了从纳米级球形到纳米级的形态转变。 当MMP在现场作用时，成型的、离散的材料可作为微米级组件的脚手架 密西西比。虽然我们之前的工作展示了使用基质金属蛋白酶反应纳米颗粒的概念验证 在急性心肌梗死中靶向传递和滞留，聚合物纳米颗粒是不可降解的，这将 限制翻译，并没有携带治疗货物。在这里，我们的目标是开发可翻译、可降解的 系统以及演示使用这种新型生物材料平台的概念验证 提供治疗急性心肌梗死的药物。 好了！

Summary Despite recent advances, heart failure (HF) continues to be the leading cause of death in the U.S., and the rest of the western world. Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF. Therefore, our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Recently there has been significant progress in the development injectable biomaterials that stimulate endogenous repair on their own or through the controlled release of additional therapeutics. This approach is attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off- target effects that plague traditional pharmaceuticals. However, the approach of direct injection of these biomaterials (either through minimally invasive surgery or percutaneous transendocardial injection) is unlikely to be translated to AMI patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic window immediately post-MI. Together, the PIs have developed a new biomaterials based approach for delivering therapeutics that would obviate the need for direct injection into the heart, which could enable intracoronary infusion, a procedure that is possible at the time of MI, or even less invasive intravenous (IV) injection. This approach involves the use of enzyme-responsive peptide-polymer amphiphilic nanoparticles, which respond to matrix metalloproteineases (MMP-2 and MMP-9) that are upregulated in heart post-MI. The nanoparticles undergo a morphological transition from nanoscale spherical- shaped, discrete materials to scaffold like, micron scale assemblies when acted upon by MMPs at the site of MI. While our previous work demonstrated proof-of-concept for the use of MMP-responsive nanoparticles for the targeted delivery and retention in an AMI, the polymeric nanoparticles were non-degradable, which would limit translation, and did not carry a therapeutic cargo. Here, we aim to develop translatable, degradable systems as well as demonstrate proof-of-concept for using this novel biomaterial platform for the targeted delivery of therapeutics for AMI. !