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瘤的定位 酶。蛋白酶降解细胞外基质和细胞基质，增加肿瘤增殖， 侵袭、转移。我们的研究重点是用组织蛋白酶 B 和尿激酶检测肿瘤 纤溶酶原激活剂，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 类型的蛋白酶，因此可以成为检测多种类型肿瘤的灵活平台技术。 为了实现我们的目标，我们建议开发一种新型造影剂，该造影剂可以被蛋白酶切割，然后 经历自发分解，最终自发形成真黑素或褐黑素。我们的对比 制剂由肽和黑色素组成，是天然的、生物相容性材料。我们自发的 可拆卸连接体用于药物输送，因此这些连接体也具有生物相容性。因此，我们的 造影剂具有最终临床转化的巨大潜力。 我们建议使用我们的黑色素生成造影剂通过非侵入性改善肿瘤定位 多光谱光声断层扫描（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。我们将开发并使用创新的动态 MSOT 成像协议来监测 肿瘤中黑色素的生成，提高了蛋白酶活性肿瘤与正常组织的特异性。 我们还建议使用我们的黑色素生成造影剂来改善手术期间的肿瘤定位。 其他研究已经开发出荧光造影剂，这些荧光造影剂可以在具有高浓度的肿瘤中被捕获或激活。 蛋白酶活性。然后可以在手术期间对这些肿瘤进行可视化，此时可以使用 荧光成像仪器。我们的技术将导致黑色素在高浓度肿瘤中积聚 蛋白酶活性，导致肿瘤变黑。简单的目视检查，无需昂​​贵的 笨重的荧光成像仪器，可以根据米色到红色识别黑色肿瘤 正常组织的背景。然后可以在手术过程中将这些黑色肿瘤从体内切除。作为一个 长期目标，我们建议 MSOT 最终可用于将蛋白酶活性肿瘤定位为深部 距手术过程中暴露的组织表面3厘米，进一步改善肿瘤的手术切除。 为了实现我们的目标，我们将合成每种造影剂，证明具有特定的裂解 酶导致黑色素的合成，并进行 Michaelis-Menten 酶动力学研究以验证 酶活性的检测。对于目标 1，我们将进行体内 MSOT 研究，以检测体内的蛋白酶活性 人类肿瘤的小鼠模型。对于目标 2，我们将使用小鼠肿瘤模型模拟光学引导手术 检测具有高黑色素积累的黑色肿瘤。我们的交付成果是追求临床的基础 翻译我们的造影剂用于临床 MSOT 检查和临床手术期间。