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

项目概要/摘要 心肌梗死（MI）仍然是世界上主要的死亡原因之一， 心肌梗死后发生的负性组织重塑导致心力衰竭（HF）。方法 需要在MI后立即治疗心脏并防止负性重塑，以改善患者的 提高长期生存率。这项提案的目标是开发一种新的治疗方法， 输送系统，以非侵入性和安全的目标治疗梗死后立即MI。等 需要一种系统来避免在递送治疗剂时发生的脱靶副作用 并且允许静脉内给药而不是直接注射到受损的 心脏组织，这是许多其他正在开发的输送系统所必需的。酶反应 纳米颗粒是一种有前途的方法。这些纳米颗粒对基质金属蛋白酶有反应 基质金属蛋白酶（MMPs），一种在心肌梗死后上调的酶，有助于推动负性重塑， 随后的HF。以前的研究表明，它们可以通过静脉注射，并会在体内积累。 梗塞这项提案旨在建立在以前的工作和开发这些纳米粒子的非- 侵入性和安全的药物输送到梗塞。这项建议的第一个目的是重新设计 本发明的目的是提供纳米颗粒以在累积后从组织中消除并评估其安全性。 可裂解的核将被并入纳米颗粒中以促进消除。核心裂解将 在MI的大鼠模型中测试之前，在体外进行评估。毒性研究将在体外进行， 通过检查炎症反应，评估肝脏和心肌细胞， 肾功能和分析血细胞计数先积累后消除， 还将在大鼠模型中评估引起心律失常的可能性。建议的第二个目的 目的是研究MMP-反应性纳米颗粒作为MMP抑制剂的载体。研究表明 MMP抑制剂限制了动物的负性重塑，但它们并不适用于 由于脱靶副作用，因此，MMP抑制剂将缀合至 通过不稳定的化学键结合纳米颗粒核心，使得在梗塞中积累后， 发布将在体外评估功能性MMP抑制剂释放。那么使用 将研究将MMP抑制剂递送至梗死并改善组织恢复的纳米颗粒。 大鼠心肌梗死模型。该提案旨在开发一种新的、非侵入性的、安全的策略， 将治疗剂递送至梗塞以支持组织修复。如果成功，这项工作将 有可能彻底改变MI治疗并显著改善MI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.