Enzyme responsive nanoparticle delivery of a small molecule MMP inhibitor following acute myocardial infarction

项目摘要 心肌梗死（MI）是心血管疾病的主要原因， 每年有605，000起新的攻击和200，000起经常性攻击。这些患者中的许多人会继续发展 心脏衰竭，并最终在诊断后五年内面临过早死亡。现行标准 护理包括外科手术和处方药物，以减轻未来对心脏的损害 并减轻另一种不良心脏事件的可能性，但它们不能治疗已经造成的损害。 已经完成了。尽管已经有许多关于各种细胞和生物材料的临床前研究 设计用于治疗MI后患者的治疗，在大多数情况下，通过心肌内给药 注射，这是一种临床上不相关的方法，因为心肌梗死后心脏太脆弱。因此 需要开发一种可在MI后立即给药的治疗剂， 对心脏的损伤通过纳米颗粒载体的靶向药物递送为许多人带来了新的希望。 小分子药物以前受到高剂量和/或溶解性差的阻碍。 以前，我们已经证明了肽-聚合物两亲物的聚集和定位 心肌梗死（MI）后心脏中的纳米颗粒。静脉注射后，这些纳米颗粒 从渗漏的脉管系统外渗到梗死区， 基质金属蛋白酶（MMPs）是降解细胞外基质的蛋白水解酶， 以暴露疏水性核心并形成微米级聚集体。基于这种坚固的纳米粒子 系统，在这里，我们通过结合一个小的 分子药物的聚合物主链。在此过程中，我们将研究药物的保存能力- 负载的纳米颗粒定位到心脏的梗塞区域，并释放生物活性的小分子， 分子MMP-抑制剂。此外，我们有兴趣提高我们的目标能力， 通过掺入心脏归巢肽（CHP）序列，纳米颗粒已经证明了特异性 定位于心肌的缺血区域。通过增加本地化，我们将能够降低 必要的有效剂量，并减少任何脱靶效应。目前还没有针对性的 可在MI的急性期施用以防止损伤的治疗剂。而MMP 用小分子药物进行抑制已经显示出减少左心室扩张和扩张 在MI之后，仍然需要局部的、非侵入性的递送到梗塞部位以使这些药物 临床上可翻译的因此，我们假设我们的靶向纳米颗粒将改善药物递送到 心肌梗死区，导致急性MI期MMP活性降低， 随着时间的推移，心脏功能得到改善。

Project Summary Myocardial infarction (MI) is a main contributor to cardiovascular disease with an annual incidence of 605,000 new attacks and 200,000 recurrent attacks annually. Many of these patients will go on to develop heart failure and ultimately face premature mortality within five years of diagnosis. Current standard of care includes surgical intervention and prescribed medications that attenuate future damage to the heart and mitigate the likelihood of another adverse cardiac event, but they do not treat the damage that has already been done. Though there have been many pre-clinical studies of various cell and biomaterial therapies designed to treat patients post-MI, in most cases they are administered via intramyocardial injections, a method that is not clinically relevant because the heart is too fragile following MI. Thus, there exists a need to develop a therapeutic that can be administered immediately after MI to prevent the extent of damage to the heart. Targeted drug delivery via nanoparticle carriers has renewed promise for many small molecule drugs that have been previously hampered by high dosages and/or poor solubility. Previously, we have demonstrated the aggregation and localization of peptide-polymer amphiphile nanoparticles in the heart following myocardial infarction (MI). Following IV injection, these nanoparticles extravasated from the leaky vasculature into the infarct where endogenous matrix metalloproteinases (MMPs), proteolytic enzymes that degrade the extracellular matrix, cleaved the MMP-responsive peptide to expose the hydrophobic core and form micron-scale aggregates. Building upon this robust nanoparticle system, here we move from a proof of concept platform to an actual therapeutic by conjugating a small molecule drug to the polymer backbone. In doing this, we will investigate the preserved ability of drug- loaded nanoparticles to localize to the infarcted region of the heart and release a biologically active small molecule MMP-inhibitor. In addition, we are interested in improving the targeting capability of our nanoparticles by incorporating a cardiac homing peptide (CHP) sequence that has demonstrated specific localization to the ischemic region of the myocardium. By increasing localization, we will be able to lower the necessary effective dose and decrease any off-target effects. There is not currently a targeted therapeutic that can be administered during the acute phase of MI to prevent damage. While MMP inhibition with small molecule drugs has been shown to decrease left ventricle dilation and expansion following MI, there remains a need for localized, non-invasive delivery to the infarct to make these drugs clinically translatable. Thus, we hypothesize that our targeting NPs will improve drug delivery to the infarcted region of the heart, resulting in decreased MMP activity in the acute MI-stage and improved cardiac function over time.