Exploiting Melanin Synthesis to Improve Tumor Detection with Multispectral Optoacoustic Tomography and Optical Guided Surgery

利用多光谱光声断层扫描和光引导手术利用黑色素合成来改善肿瘤检测

• 批准号: 10152589
• 负责人: Mark David Pagel
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152589
• 关键词: Animals; Biocompatible Materials; Biological Markers; Caliber; Cathepsins B; Cleaved cell; Clinical; Contrast Media; Detection; Drug Delivery Systems; Drug usage; Environment; Enzyme Kinetics; Enzymes; Excision; Extracellular Matrix; Extracellular Matrix Degradation; Foundations; Generations; Goals; Image; Left; Malignant Neoplasms; Melanins; Methodology; Modeling; Monitor; Mus; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Optics; Patients; Peptide Hydrolases; Peptides; Peripheral; Polymers; Protocols documentation; Research; Research Personnel; Research Project Grants; Solid Neoplasm; Specificity; Speed; Surface; Surgeon; Surgical Oncology; Technology; Testing; Tissues; Urokinase; Visual; biomaterial compatibility; cancer diagnosis; cancer imaging; clinical translation; dopachrome; enzyme activity; eumelanin; extracellular; flexibility; fluorescence imaging; fluorophore; human model; improved; in vivo; innovation; instrument; instrumentation; malignant breast neoplasm; molecular imaging; mouse model; optical imaging; optoacoustic tomography; overexpression; pheomelanin; photoacoustic imaging; pre-clinical; tumor; tumor microenvironment

Our goal is to improve the localization of solid tumors that express and secrete high levels of protease enzymes. Proteases degrade the extracellular matrix and cellular stroma, increasing tumor proliferation, invasion, and metastasis. Our research will focus on the detection of tumors with cathepsin B and urokinase Plasminogen Activator, which are protease biomarkers of malignant tumors. Yet our technology can detect many types of proteases, and therefore can be a flexible platform technology for detecting many types of tumors. To meet our goal, we propose to develop a new type of contrast agent that is cleaved by a protease, then undergoes spontaneous disassembly, and finally spontaneously forms eumelanin or pheomelanin. Our contrast agents consist of peptides and melanins that are natural, biocompatible materials. Our spontaneous disassembling linkers are used for drug delivery, so that these linkers are also biocompatible. Therefore, our contrast agents have strong potential for eventual clinical translation. We propose to use our melanin-generating contrast agents to improve tumor localization with noninvasive Multispectral Optoacoustic Tomography (MSOT), also known as photoacoustic imaging. Pre-clinical MSOT can image an entire torso of mouse tumor models, and clinical MSOT has been used to image many tumor types including breast cancer. We will develop and use an innovative dynamic MSOT imaging protocol that will monitor the generation of melanins in tumors, which improves the specificity of protease-active tumors vs. normal tissues. We also propose to use our melanin-generating contrast agents to improve tumor localization during surgery. Other research has developed fluorescent contrast agents that are trapped or activated in tumors with high protease activity. These tumors can then be visualized during surgery, when the tumors can be imaged with fluorescence imaging instrumentation. Our technology will cause melanins to accumulate in tumors with high protease activity, causing the tumors to become black. Simple visual inspection, without expensive and cumbersome fluorescence imaging instrumentation, can identify the black tumors against the beige-to-red background of normal tissues. These black tumors can then be excised from the body during surgery. As a longer-term goal, we propose that MSOT could eventually be used to localize protease-active tumors as deep as 3 cm from tissue surfaces that are exposed during surgery, further improving surgical resection of tumors. To meet our objectives, we will synthesize each contrast agent, demonstrate that cleavage with a specific enzyme results in synthesis of a melanin, and perform Michaelis-Menten enzyme kinetics studies to validate the detection of enzyme activity. For Aim 1, we will perform in vivo MSOT studies to detect protease activities in mouse models of human tumors. For Aim 2, we will simulate optical guided surgery with mouse tumor models to detect black tumors that have high melanin accumulation. Our deliverable is a foundation for pursuing clinical translation of our contrast agents for clinical MSOT exams and during clinical surgery.

我们的目标是改善表达和分泌高水平蛋白酶的实体肿瘤的定位。 酵素。蛋白水解酶降解细胞外基质和细胞间质，促进肿瘤增殖， 侵袭和转移。我们的研究将重点放在用组织蛋白酶B和尿激酶检测肿瘤上 纤溶酶原激活物，它们是恶性肿瘤的蛋白酶生物标志物。然而我们的技术可以检测到许多 因此，它可以成为检测多种类型肿瘤的灵活平台技术。 为了达到我们的目标，我们提议开发一种新型的造影剂，这种造影剂可以被蛋白酶切割，然后 经过自发的分解，最后自发地形成真黑素或褐黑素。我们的对比 制剂由多肽和黑色素组成，这些都是天然的、生物兼容的材料。我们自发的 可拆卸接头用于药物输送，因此这些接头也是生物相容的。因此，我们的 造影剂对最终的临床转化有很大的潜力。 我们建议使用我们的黑色素生成造影剂来改善肿瘤的非侵入性定位。 多光谱光声层析成像(MSOT)，也称为光声成像。临床前MSOT可以 对小鼠肿瘤模型的整个躯干进行成像，临床MSOT已用于对多种肿瘤类型进行成像 包括乳腺癌。我们将开发和使用创新的动态MSOT成像协议，该协议将监测 黑色素在肿瘤中的产生，与正常组织相比，它提高了蛋白水解酶活性肿瘤的特异性。 我们还建议在手术中使用我们的黑色素生成造影剂来改善肿瘤的定位。 其他研究已经开发出荧光造影剂，这种造影剂可以捕获或激活高密度的肿瘤。 水解酶活性。然后，这些肿瘤可以在手术中被可视化，当肿瘤可以用 荧光成像仪器。我们的技术将导致黑色素在高密度的肿瘤中积聚 蛋白水解酶活性，导致肿瘤变黑。简单的视觉检查，不需要昂贵和 笨重的荧光成像仪器，可以针对米色到红色的黑色肿瘤进行识别 正常组织的背景。然后，这些黑色肿瘤可以在手术过程中从体内切除。作为一名 更长期的目标是，我们提出MSOT最终可能被用来定位蛋白水解酶活性的肿瘤 距离手术中暴露的组织表面3厘米，进一步改善了手术切除肿瘤的效果。 为了达到我们的目标，我们将合成每一种造影剂，展示与特定的 酶导致黑色素的合成，并进行米氏酶动力学研究，以验证 酶活性的检测。对于目标1，我们将在体内进行MSOT研究，以检测 人类肿瘤的小鼠模型。对于目标2，我们将用小鼠肿瘤模型模拟光学引导手术 以检测黑色素积累较多的黑色肿瘤。我们的交付成果是追求临床的基础 翻译我们用于临床MSOT检查和临床手术的造影剂。