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诱因，每年的发病率为 每年60.5万次新攻击和20万次反复攻击。这些患者中的许多人将继续发展 心力衰竭，最终在确诊后五年内面临过早死亡。现行标准 护理包括手术干预和处方药物，以减轻未来对心脏的损害 并减少发生另一次不良心脏事件的可能性，但它们不能治疗 已经做过了。尽管已经有许多关于各种细胞和生物材料的临床前研究 用于治疗心肌梗死后患者的治疗，大多数情况下是通过心肌内给药 注射是一种临床上没有意义的方法，因为心肌梗死后心脏太脆弱了。因此，在那里 有必要开发一种治疗方法，可以在心肌梗死后立即给予，以防止范围 对心脏的损害。通过纳米载体的靶向药物输送为许多人带来了新的希望 小分子药物以前因剂量大和/或溶解性差而受阻。 在此之前，我们已经演示了多肽-聚合物两亲分子的聚集和定位 心肌梗死(MI)后心脏内的纳米颗粒。静脉注射后，这些纳米颗粒 从渗漏的血管渗出进入梗死区，内源性基质金属蛋白酶 基质金属蛋白酶(MMPs)是一种降解细胞外基质的蛋白水解酶，它能裂解基质金属蛋白酶反应性多肽 以露出疏水核心并形成微米级的聚集体。以这种坚固的纳米颗粒为基础 系统，在这里，我们从概念验证平台转移到实际的治疗通过共轭小 分子药物到聚合物主链上。为此，我们将调查药物的保存能力- 负载的纳米颗粒定位于心脏梗死区域并释放具有生物活性的小分子 分子基质金属蛋白酶抑制因子。此外，我们有兴趣提高我们的目标能力 通过掺入心脏归巢多肽(CHP)序列获得纳米颗粒，该序列已证明 定位于心肌缺血区。通过增加本地化，我们将能够降低 必要的有效剂量，并减少任何偏离目标的影响。目前没有有针对性的 可在急性心肌梗塞急性期给予治疗，以防止损害。而明尼阿波利斯 小分子药物的抑制作用已被证明可以减少左心室的扩张和扩张。 在心肌梗塞后，仍然需要局部的、非侵入性的给药来制造这些药物。 临床上可翻译的。因此，我们假设我们的靶向NPs将改善药物对 心肌梗死区，导致急性心肌梗死时基质金属蛋白酶活性降低； 随着时间的推移，心功能得到了改善。

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.