Luminescent Oxygen Nanosensors for Tumor Hypoxia Imaging

用于肿瘤缺氧成像的发光氧纳米传感器

• 批准号: 8276440
• 负责人: CASSANDRA L FRASER
• 金额: $ 39.65万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8276440
• 关键词: Affect; Amines; Biochemical Markers; Biodistribution; Biological Process; Biotin; Boron; Breast Cancer Cell; Cancer Biology; Cell model; Cells; Cessation of life; Collagen; Color; Cyclophosphamide; Detection; Diagnosis; Disease; Drug Delivery Systems; Drug effect disorder; Dyes; Environment; Fiber Optics; Fluorescence; Folate; Goals; Healed; Health; Hemoglobin; Hypoxia; Image; Imaging technology; In Vitro; Life; Light; Lighting; Malignant Neoplasms; Mammary gland; Maps; Measurement; Measures; Medical; Medicine; Methodology; Methods; Modeling; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Optics; Organism; Outcome; Oxygen; Oxygen Consumption; Partial Pressure; Penetration; Pharmaceutical Preparations; Play; Polymers; Population; Protocols documentation; Radiation; Radiation therapy; Resolution; Role; Specificity; Structure; System; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Oxygenation; Validation; Work; absorption; angiogenesis; cancer care; chemotherapy; cost effective; healing; hypoxia inducible factor 1; imaging modality; improved; in vivo; innovation; insight; luminescence; malignant breast neoplasm; monolayer; mouse model; nanoparticle; nanosensors; optical imaging; phosphorescence; poly(lactic acid); pre-clinical; preclinical study; ratiometric; resistance mechanism; response; sensor; success; therapy resistant; tissue oxygenation; tool; tumor; tumor progression; whole body imaging

DESCRIPTION (provided by applicant): Oxygenation plays a critical role in health and medicine. Deficits or excesses in cells, tissues and organisms are associated with disease, damage, poor healing, and even death. For example, hypoxia is implicated in cancer progression, metastasis, and resistance to therapies. Hypoxia inducible factor 1 (HIF-1) expression in low oxygen environments accelerates angiogenesis and promotes tumor survival, and radiation and drug treatments can be less effective when reactive oxygen is not present to enhance the tumor damage or when hypoxia-induced changes in the tumor microenvironment otherwise affect drug delivery and action. Despite the importance of oxygen partial pressure (pO2) to biomedicine, its assessment is often limited to oxygen consumption rate (OCR) measurements, invasive probes, or expensive imaging modalities. Often methods provide only average values for whole populations of cells, or are restricted to single point measurements in space or time. The long-term goal of this project is to develop a versatile material set and platform of pO2 imaging technologies that can enhance preclinical studies and aid in diagnosis, treatment and surgery in many medical contexts. Building upon success in proof of concept studies and the strengths of our team in materials synthesis, imaging, and cancer biology, the objective of this application is to develop dualemissive difluoroboron ?-diketonate-poly(lactic acid) (BF2bdkPLA) dye-polymer nanoparticles (BNPs) in conjunction with imaging methodologies for luminescence detection and ratiometric O2 sensing in breast cancer in vitro and in vivo mouse models. This objective will be accomplished by pursuing the following specific aims: 1) BNP dyes will be chemically modified for broad range emission color tuning and oxygen sensitivity modulation; imaging methods will be developed for their use in in vitro ratiometric O2 sensing (i.e. both fluorescence (F) and phosphorescence (P) detection). 2) BNP polymers will be adapted for passive and active targeting for pO2 monitoring with improved spatial specificity; targeted BNPs will be investigated in vitro and in vivo. 3) BNP hypoxia imaging agents will be tested for their ability to detect tumors, and to monitor tumor progression and radiation and chemotherapy response over time in a mouse mammary window model. The proposed cost- effective technology is innovative because it enables dynamic hypoxia imaging with improved combined spatial and temporal resolution compared to existing approaches with a modular, tunable, synthetically accessible materials platform. The expected outcome is a versatile oxygen nanosensor technology in conjunction with common optical imaging modalities to quantify pO2 in cells, tissues and in vivo. BNPs with greater specificity, tissue penetration of light, and multiplexing capability will result. This work will have a positive impact on cancer car because it will better illuminate the relationships between hypoxia, cancer progression, and treatment protocols. Ultimately, BNPs will shed light on many medical challenges by helping to map relationships between oxygenation and biological function. This is already being realized. PUBLIC HEALTH RELEVANCE: Tissue oxygenation plays a critical role in diseases, health, and healing, but it is difficult to measure with good spatial and temporal resolution. We plan to develop oxygen nanosensors and associated optical detection methods for quantitative, high-resolution hypoxia imaging that promises new insight into the relationships between tumor oxygenation and breast cancer biology, detection and treatment protocols.

描述（由申请人提供）：氧合在健康和医学中起着关键作用。细胞、组织和生物体的缺陷或过度与疾病、损伤、愈合不良甚至死亡有关。例如，缺氧与癌症进展、转移和对治疗的抗性有关。低氧诱导因子1（HIF-1）在低氧环境中的表达加速血管生成并促进肿瘤存活，并且当不存在活性氧以增强肿瘤损伤时或当低氧诱导的肿瘤微环境变化以其他方式影响药物递送和作用时，放射和药物治疗可能不太有效。尽管氧分压（pO 2）对生物医学很重要，但其评估通常仅限于耗氧率（OCR）测量、侵入性探头或昂贵的成像方式。通常，方法仅提供整个细胞群的平均值，或者仅限于空间或时间上的单点测量。该项目的长期目标是开发一种多功能的pO 2成像技术材料集和平台，可以增强临床前研究，并在许多医学背景下辅助诊断、治疗和手术。基于概念验证研究的成功以及我们团队在材料合成、成像和癌症生物学方面的优势，本申请的目标是开发双发射二氟硼？二酮-聚乳酸（BF 2bdkPLA）染料-聚合物纳米颗粒（BNP）结合成像方法用于乳腺癌体外和体内小鼠模型中的发光检测和比率O2传感。这一目标将通过追求以下具体目标来实现：1）BNP染料将被化学修饰以用于宽范围发射颜色调谐和氧敏感性调制;将开发成像方法以用于体外比率O2传感（即荧光（F）和磷光（P）检测）。2)BNP聚合物将适用于pO 2监测的被动和主动靶向，具有改善的空间特异性;靶向BNP将在体外和体内进行研究。3)将在小鼠乳腺窗模型中测试BNP缺氧显像剂检测肿瘤的能力，以及随时间监测肿瘤进展和放疗和化疗反应的能力。所提出的具有成本效益的技术是创新性的，因为与具有模块化、可调、合成可访问材料平台的现有方法相比，其能够实现具有改进的组合空间和时间分辨率的动态缺氧成像。预期的结果是一种多功能的氧纳米传感器技术，结合常见的光学成像模式，以量化细胞，组织和体内的pO 2。具有更高特异性的BNP， 光和多路复用能力将产生。这项工作将对癌症产生积极的影响，因为它将更好地阐明缺氧，癌症进展和治疗方案之间的关系。最终，BNP将通过帮助绘制氧合和生物功能之间的关系来揭示许多医学挑战。这一点已经实现。 公共卫生关系：组织氧合作用在疾病、健康和愈合中发挥着关键作用，但很难以良好的空间和时间分辨率进行测量。我们计划开发氧纳米传感器和相关的光学检测方法，用于定量，高分辨率缺氧成像，有望对肿瘤氧合与乳腺癌生物学，检测和治疗方案之间的关系有新的见解。