MMP Responsive Nanoparticles for Treating Acute Myocardial Infarction

总结 尽管最近取得了进展，但心力衰竭（HF）仍然是美国的主要死亡原因，等人 西方世界。大约37%的心肌梗死（MI）患者将在1年内死于HF， 在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550 K 美国人将有一个新的MI，和~ 200 K将有一个复发性MI，导致大量的患者遭受痛苦 从HF因此，我们的长期目标是开发新的、微创的、靶向的生物材料 治疗急性心肌梗死（AMI）的基础疗法，从而限制了进展至 HF。最近，在开发可注射生物材料方面取得了重大进展， 内源性修复本身或通过控制释放额外的治疗剂。这种方法 由于潜在的治疗方法可以通过导管以最低限度的侵入性输送， 并且成本有效，并且在治疗递送的情况下，将提供限制全身性关闭的靶向递送。 针对困扰传统药物的影响。然而，直接注射这些药物的方法 生物材料（通过微创手术或经皮经血管内注射）不太可能 由于注射程序存在严重的安全性问题， 错过心肌梗死后即刻的关键治疗窗。PI们共同开发了一种新的 用于递送治疗剂的基于生物材料的方法，该方法将消除直接注射到患者体内的需要。 心脏，这可以使冠状动脉内输注，这是一个在MI时可能的程序，甚至更少 侵入性静脉内（IV）注射。这种方法涉及使用酶响应肽聚合物 两亲性纳米颗粒，其响应于基质金属蛋白酶（MMP-2和MMP-9）， 心肌梗死后心脏中表达上调。纳米颗粒经历了从纳米级球形- 当MMP作用于细胞表面时， MI.虽然我们以前的工作证明了使用MMP-响应性纳米颗粒用于 在AMI中的靶向递送和保留，聚合物纳米颗粒是不可降解的，这将 限制翻译，并且没有携带治疗货物。在这里，我们的目标是开发可翻译的，可降解的 系统，并证明了使用这种新型生物材料平台进行靶向治疗的概念验证。 用于AMI的治疗剂的递送。 !

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. !