NEAR INFRARED IMAGING OF MMP-2/MM-9 WITH A HIGHLY SPECIFIC OPTICAL PROBE

描述（由申请人提供）：基质金属蛋白酶（MMP）通常以高水平存在于癌症如皮肤、乳腺、甲状腺、子宫颈、肺、结肠和前列腺的肿瘤中，但在正常组织中不存在。MMPs是一种酶，能够咀嚼蛋白质屏障，将原发性肿瘤固定在原位。一旦这些屏障被降解，肿瘤就可以扩散或转移到全身。我们正在设计一种探针，给病人使用，在被基质金属蛋白酶降解之前，它将保持不可见。当它被咬成两半后，探针就会亮起来。我们将用光学成像设备捕获和测量光，并知道肿瘤含有高水平的MMPs。主要的制药公司目前正在开发药物，抑制MMPs的作用，从而减缓或完全阻止转移。如果我们成功了，探针可以用来决定是否开始MMP抑制剂治疗，并在治疗开始后进行监测。它也可以用来确定哪些肿瘤可能转移。用于光学成像的设备相对便宜且不复杂。病人可能会在医生的办公室接受扫描。为了测试探针是否有效照亮肿瘤，我们将执行以下目标。目标1：探针将从市售的起始材料制备，如果需要，从起始材料中分离，并测试其纯度目的2：在动物模型中测试之前，探针将以各种方式进行测试，以显示它们确实会被MMP咀嚼成两半，并释放出可视化活体中生长的肿瘤所需的光量。还将测试探针的稳定性和毒性。目标3：最后，将在动物模型中测试探针，以观察肿瘤是否亮到足以量化的程度。将使用各种实验（对照）来确保观察到的光确实是由于MMP作用而不是来自其他来源。公共卫生相关性这项研究的目标是开发光学上不可见的药物，直到它们遇到肿瘤并在其存在时发光。最终，这些药物将允许快速和非侵入性或微创诊断癌症。

DESCRIPTION (provided by applicant): Matrix metallo-proteinases (MMPs) are often present in high levels in cancer such as tumors of the skin, breast, thyroid, cervix, lung, colon and prostate, but absent in normal tissues. MMPs are enzymes that are capable of chewing through the protein barriers that hold the primary tumor in its place. Once these barriers are degraded, the tumor can spread, or metastasize, throughout the body. We are designing a probe, to administer to the patient, that will remain invisible until it is degraded by the MMPs. After it is chewed in half, the probe will light up. We will capture and measure the light with optical imaging equipment and know that the tumor contains high levels of MMPs. The major pharmaceutical companies are currently developing drugs that will inhibit the action of the MMPs, thus slowing metastasis or stopping it altogether. If we are successful, the probe could be used to decide whether to initiate MMP inhibitor therapy and to monitor the therapy once it has begun. It could also be used to identify which tumors are likely to metastasize. The equipment used for optical imaging is relatively inexpensive and uncomplicated. A patient would likely be scanned at the office of their doctor. To test whether the probes will be effective in lighting up tumors we will perform the following Aims. Aim 1: The probes will be prepared from commercially available starting materials, separated from the starting materials if necessary, and tested for their purity Aim 2: Before testing in animal models, the probes will be tested in a variety of ways to show that they will indeed be chewed in half by MMPs and release the quantity of light needed to visualize a tumor growing in a living being. The stability and toxicity of the probes will be tested as well. Aim 3: Finally the probes will be tested in an animal model to see whether the tumors light up to an extent that the light is significant enough to be quantified. A variety of experiments (controls) will be used to make sure that the light observed is indeed due to MMP action and not from another source. PUBLIC HEALTH RELEVANCE The goal of this research is to develop pharmaceuticals that are optically invisible until they encounter a tumor and light up in its presence. Ultimately, these agents will allow for rapid and non-invasive or minimally invasive diagnosis of cancer.