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（MMPs）通常在皮肤、乳腺、甲状腺、宫颈、肺、结肠和前列腺等肿瘤中以高水平存在，但在正常组织中不存在。MMPs是一种酶，它能够冲破将原发肿瘤固定在原位的蛋白质屏障。一旦这些屏障被破坏，肿瘤就会扩散或转移到全身。我们正在设计一种探针，给病人使用，它在被MMPs降解之前是不可见的。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。各大制药公司目前正在开发抑制MMPs作用的药物，从而减缓转移或完全停止转移。如果我们成功了，探针可以用来决定是否启动MMP抑制剂治疗，并在治疗开始后监测治疗。它还可以用来识别哪些肿瘤可能转移。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。为了测试探针是否能有效地照亮肿瘤，我们将进行以下目的。目标1：探针将从市买的起始材料中制备，必要时从起始材料中分离，并测试其纯度。目标2：在动物模型测试之前，探针将以各种方式进行测试，以表明它们确实会被MMPs咀嚼成两半，并释放出可视化肿瘤生长所需的光量。探测器的稳定性和毒性也将被测试。目标3：最后，探针将在动物模型中进行测试，以观察肿瘤是否亮到足以量化的程度。将使用各种实验（控制）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。这项研究的目标是开发一种药物，这种药物在遇到肿瘤之前在光学上是看不见的，并且在肿瘤出现时发光。最终，这些药物将允许快速、无创或微创诊断癌症。

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.