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: 9978211
• 负责人: Mark David Pagel
• 金额: $ 24.3万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978211
• 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; 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， 入侵和转移。我们的研究将重点放在血管蛋白酶B和尿激酶的肿瘤检测上 纤溶酶原激活剂，它们是恶性肿瘤的蛋白酶生物标志物。但是我们的技术可以检测到许多 蛋白酶的类型，因此可以是一种灵活的平台技术，用于检测许多类型的肿瘤。 为了满足我们的目标，我们建议开发一种新型的对比剂，该剂被蛋白酶裂开，然后 自发拆卸，最后自发形成eumelanin或pheomelanin。我们的对比 药物由天然，生物相容性材料的肽和黑色素组成。我们的自发 拆卸连接器用于药物输送，因此这些连接器也具有生物相容性。因此，我们的 对比剂具有最终临床翻译的强大潜力。 我们建议使用我们的黑色素生成对比剂来改善无创的肿瘤定位 多光谱光声断层扫描（MSOT），也称为光声成像。临床前MSOT可以 图像小鼠肿瘤模型的整个躯干，以及临床MSOT已被用于成像许多肿瘤类型 包括乳腺癌。我们将开发和使用创新的动态MSOT成像协议，该协议将监视 肿瘤中黑色素的产生，可改善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对比剂来改善手术过程中的肿瘤定位。 其他研究已经开发了荧光对比剂，这些荧光剂被困在高肿瘤中 蛋白酶活性。然后，可以在手术中可视化这些肿瘤，当时可以与肿瘤成像 荧光成像仪器。我们的技术将导致黑色素在高肿瘤中积聚 蛋白酶活性，导致肿瘤变成黑色。简单的视觉检查，无昂贵， 繁琐的荧光成像仪器可以鉴定出针对米色到红色的黑色肿瘤 正常组织的背景。然后，可以在手术期间从身体中切除这些黑色肿瘤。作为 长期目标，我们建议MSOT最终可以将蛋白酶活性肿瘤定位为深 在手术期间暴露的组织表面3厘米处，进一步改善了肿瘤的手术切除。 为了实现我们的目标，我们将综合每个对比剂，证明乳沟具有特定的 酶会导致黑色素的合成，并进行迈克利斯 - 门en酶动力学研究以验证 检测酶活性。对于AIM 1，我们将进行体内MSOT研究以检测蛋白酶的活动 人类肿瘤的小鼠模型。对于AIM 2，我们将使用小鼠肿瘤模型模拟光学指导手术 检测黑色素积累高的黑肿瘤。我们的可交付款是追求临床的基础 临床MSOT检查和临床手术期间的对比剂的翻译。