Enzyme-responsive Polymeric Micelles for Targeted Therapeutic Delivery to the Heart Post-myocardial Infarction

项目摘要/摘要 心肌梗死(MI)仍然是世界上主要的死亡原因之一。 与心肌梗死后发生的负性组织重塑并导致心力衰竭(HF)有关。方法，以 心肌梗死后立即治疗心脏和防止负性重构是改善患者状况的必要措施 结果和提高长期存活率。这项提议的目标是开发一种新的治疗方法 急性心肌梗死后立即无创、安全地靶向治疗心肌梗死。是这样的 需要一个系统来避免在提供治疗药物时发生的偏离目标的副作用 并允许静脉给药，而不是直接注射到受损的 心脏组织是许多其他正在开发的递送系统所必需的。酶反应 纳米粒子是一种很有前途的方法。这些纳米颗粒对基质金属蛋白酶有反应。 (MMPs)，这种酶在心肌梗死后上调，有助于推动负向重构和 随后的高频。以前的研究表明，它们可以静脉注射，并在体内蓄积 脑梗塞。这项提议寻求在以前工作的基础上，开发这些纳米颗粒用于非 具有侵入性且安全的药物输送至梗塞部位。这项建议的第一个目标是重新设计 纳米粒可在蓄积后从组织中消除，并评估其安全性。 一个可切割的核心将被结合到纳米颗粒中，以便于消除。核心卵裂将 在心肌梗死大鼠模型上进行测试之前，在体外进行评估。毒性研究将在体外进行， 在动物体内通过检查炎症反应，评估肝脏和 肾功能，并分析血细胞计数。先积累后消除，以及 在大鼠模型中也将评估导致心律失常的可能性。该提案的第二个目的是 目的是研究可响应基质金属蛋白酶的纳米颗粒作为基质金属蛋白酶抑制剂的载体。研究表明 基质金属蛋白酶抑制剂限制了动物的负性重塑，但它们并不适用于 由于非靶标副作用，在人类中的全身使用。因此，基质金属蛋白酶抑制剂将结合到 纳米颗粒的核心通过不稳定的化学键，因此在脑梗塞中积累后，抑制物是 释放了。功能性基质金属蛋白酶抑制剂的释放将在体外进行评估。然后才能使用 将研究纳米颗粒将基质金属蛋白酶抑制剂输送到梗死区并改善组织恢复 心肌梗死大鼠模型。该建议旨在开发一种新的、非侵入性的、安全的策略来针对 向梗死区输送治疗性药物以支持组织修复。如果成功，这项工作将具有 有可能给心肌梗死治疗带来革命性的变化，并显著改善心肌梗死患者的生活。

Project Summary/Abstract Myocardial infarction (MI) continues to be one of the leading causes of death in the world due to the negative tissue remodeling that takes place post-MI and leads to heart failure (HF). Methods to treat the heart immediately after MI and prevent negative remodeling are needed to improve patient outcomes and increase long-term survival. The goal of this proposal is to develop a novel therapeutic delivery system to non-invasively and safely target treatment to the infarct immediately after MI. Such a system is needed to avoid the off-target side effects that occur when therapeutics are delivered systemically and to allow for intravenous administration rather than direct injection into the damaged heart tissue as is necessary for many other delivery systems being developed. Enzyme-responsive nanoparticles are a promising approach. These nanoparticles respond to matrix metalloproteinases (MMPs), enzymes that are up regulated in the infarct post-MI and help drive negative remodeling and subsequent HF. Previous work showed that they can be injected intravenously and will accumulate in the infarct. This proposal seeks to build on previous work and develop these nanoparticles for non- invasive and safe drug delivery to the infarct. The first aim of this proposal is to redesign the nanoparticles to provide for elimination from the tissue after accumulation and to assess their safety. A cleavable core will be incorporated into the nanoparticles to facilitate elimination. Core cleavage will be assessed in vitro prior to testing in a rat model of MI. Toxicity studies will be done in vitro with heart muscle cells and in the animals by checking for an inflammatory response, evaluating liver and kidney function, and analyzing blood cell counts. Accumulation followed by elimination and the potential to cause arrhythmia will also be assessed in the rat model. The second aim of the proposal is to study the MMP-responsive nanoparticles as a delivery vehicle for MMP inhibitors. Studies show that MMP inhibitors limit the negative remodeling in animals but they have not been amenable to systemic use in humans because of off-target side effects. Thus, MMP inhibitors will be conjugated to the nanoparticle core by a labile chemical bond so that after accumulation in the infarct the inhibitor is released. Functional MMP inhibitor release will be assessed in vitro. Then the ability to use the nanoparticle to deliver the MMP inhibitor to the infarct and improve tissue recovery will be studied in the rat model of MI. This proposal aims to develop a novel, non-invasive, and safe strategy to target delivery of a therapeutic to the infarct to support tissue repair. If successful, this work has the potential to revolutionize MI treatment and significantly improve the lives of MI patients.