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