Iron Oxide Based Polymer Nanocomplex for Functional Detection of Atherosclerosis

描述(申请人提供)：几乎所有的人类都有动脉粥样硬化斑块，但只有一小部分人会经历它最危险的影响-心脏病发作或中风。动脉粥样硬化占全球死亡人数的30%，给美国带来的经济负担超过了所有癌症的总和，据估计，美国每年的经济负担为3000亿美元。减轻负担和限制大量死亡的关键是确定我们中的哪些人处于危险之中，这样他们就可以接受药物治疗，以防止心脏病发作、中风和死亡。医生依靠从磁共振成像(MRI)等成像研究中获得的信息来做出治疗决策，旨在提高患者的生活质量和寿命。通过这个项目，我们的目标是创造一种核磁共振造影剂，更有效地检测导致心脏病发作和中风的最危险的斑块。这里提出的研究旨在通过创造一种造影剂来填补我们评估患者心脏病发作和中风风险的临床能力的空白，该造影剂能够通过在动脉粥样硬化中的一个关键过程-氧化应激触发-开关来功能性地确定斑块的严重性。当氧化应激过程中存在的超氧化物分解聚合物涂层时，在疾病部位的磁共振图像上就可以看到造影剂，直到这一点为止，聚合物涂层已经掩盖了造影剂。首先，我们将创建并评估一种由聚合物涂层中屏蔽的造影剂组成的纳米颗粒。聚合物涂层使造影剂对MR来说是不可见的，这是我们设计中所希望的，直到造影剂到达疾病部位。其次，我们将评估聚合物涂层是否在超氧化物分子(类似于动脉粥样硬化中存在的分子)存在的情况下解体，从而使造影剂在MRI中可见。第三，我们将评估在存在人类细胞产生的超氧化物的情况下，纳米颗粒是否表现出同样的超氧化物触发对比。我们还将评估纳米颗粒对人类细胞的毒性水平。通过这些步骤，我们希望将该领域推向：通过基于功能的对比机制更准确地评估斑块严重程度，更知情的临床决策，并最终改善患者健康。

DESCRIPTION (provided by applicant): Nearly all humans have atherosclerotic plaque, but only a subset of us will experience its most perilous effects-a heart attack or stroke. Atherosclerosis accounts for thirty percent of worldwide deaths and brings a financial burden greater than all cancers combined an estimated $300 billion per year in the United States. The key to lessening the burden and limiting the vast number of deaths is to determine which of us are at risk so they can be medically treated to prevent heart attack, stroke, and death. Doctors rely on information gained from imaging studies such as magnetic resonance imaging (MRI) to make treatment decisions aimed at improving patient quality of life and lifespan. With this project, we aim to create a contrast agent for MRI that more effectively detects the most dangerous plaques that cause heart attacks and strokes. The studies proposed here are aimed at filling the void in our clinical ability to assess patient risk for heart attack and stroke by creating a contrast agent capable of functionally determining plaque severity with an 'on-switch' triggered by a critical process in atherosclerosis known as oxidative stress. The contrast agent becomes visible on the MR image at the disease site when superoxides present during oxidative stress disassemble the polymer coating that up until the point had masked the contrast agent. First, we will create and evaluate a nanoparticle comprised of a contrast agent shielded within a polymer coating. The polymer coating makes the contrast agent invisible to MR, as is desired in our design until such time as the agent reaches the disease site. Second, we will evaluate whether the polymer coating disintegrates in the presence of superoxide molecules (similar to those present in atherosclerosis) in a way that allows the contrast agent to become visible to MRI. Third, we will evaluate whether the nanoparticles exhibit the same superoxide-triggered contrast in the presence of superoxides produced by human cells. We will also evaluate the levels of toxicity of the nanoparticle to human cells. With these steps, we expect to move the field towards: more accurate assessment of plaque severity via a functionally-based contrast mechanism, better informed clinical decisions, and ultimately improved patient health.