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

用于心肌梗死后心脏靶向治疗的酶响应聚合物胶束

• 批准号: 9259545
• 负责人: Andrea J Luthi
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259545
• 关键词: Acute myocardial infarction; Adverse effects; Animal Model; Animals; Arrhythmia; Attenuated; Biocompatible Materials; Biological Assay; Blood Cell Count; Cardiac Myocytes; Cause of Death; Cells; Cessation of life; Cicatrix; Clinical; Development; Digestion; Drug Delivery Systems; Drug Targeting; Enzymes; Esters; Exhibits; Extracellular Matrix; Formulation; Gelatinase B; Goals; Heart; Heart failure; Human; Hydrogels; Hydrophobicity; In Vitro; Infarction; Inflammatory Response; Inhibition of Matrix Metalloproteinases Pathway; Injectable; Injection of therapeutic agent; Intravenous; Laboratories; Lead; Left Ventricular Remodeling; Left ventricular structure; Life Expectancy; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Metalloproteinase Gene; Methods; Micelles; Modeling; Morphology; Myocardial Infarction; Myocardium; Outcome; Patient-Focused Outcomes; Patients; Peptides; Physiology; Polymers; Process; Prodrugs; Public Health; Rattus; Recovery; Renal function; Research; Safety; Side; System; Testing; Therapeutic; Tissues; Toxic effect; Translations; Vertebral column; Work; cardiogenesis; chemical bond; copolymer; cytokine; design; experience; hydrophilicity; improved; in vivo; inhibitor/antagonist; injury and repair; innovation; intravenous administration; liver function; nanoparticle; novel; novel therapeutics; prevent; repaired; response; small molecule inhibitor; success; targeted delivery; targeted treatment; tissue repair

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.

项目摘要/摘要 心肌梗塞（MI）仍然是世界上主要的死亡原因之一 进行MI后发生的负组织重塑并导致心力衰竭（HF）。方法 MI后立即治疗心脏并预防负重塑以改善患者 结果并增加长期生存。该建议的目的是开发一种新颖的治疗性 在MI之后，将系统递送到非侵入性，安全地靶向梗塞。这样的 需要一个系统以避免交付治疗时发生的脱靶副作用 系统地并允许静脉内给药而不是直接注射到受损的 对于许多其他正在开发的输送系统所需的心脏组织。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反应 （MMP），在MI后梗塞中受到调节的酶，并有助于驱动负重塑和 随后的HF。先前的工作表明它们可以静脉注射，并会积聚 梗塞。该建议旨在以先前的工作为基础，并为非 - 侵入性和安全的药物输送到梗塞。该提议的第一个目的是重新设计 纳米颗粒积累后可以从组织中消除并评估其安全性。 可切合的核心将纳入纳米颗粒以促进消除。核心裂解会 在MI大鼠模型中进行测试之前，请在体外评估。毒性研究将在体外进行 心肌细胞和动物中的炎症反应，评估肝脏和 肾功能和分析血细胞计数。积累，然后消除 引起心律不齐的潜力也将在大鼠模型中进行评估。提案的第二个目标 是研究MMP响应性纳米颗粒作为MMP抑制剂的递送工具。研究表明 MMP抑制剂限制了动物的负重塑，但它们不适合 由于靶向副作用，因此在人类中的系统用途。因此，MMP抑制剂将被连接到 通过不稳定的化学键，纳米颗粒核心，因此在梗塞中积累后，抑制剂为 发行。功能性MMP抑制剂释放将在体外评估。然后能够使用 纳米颗粒将MMP抑制剂传递到梗死并改善组织恢复 MI的大鼠模型。该建议旨在制定一种新颖，无创和安全的策略来针对目标 将治疗性递送到梗塞以支持组织修复。如果成功，这项工作将有 有可能改变MI治疗并显着改善MI患者的生活。