A Quantitative Optical Sensor to Monitor Pre-Clinical Tumor Vascular Physiology

血管生成和缺氧可以显著影响治疗效果和存活肿瘤细胞的行为。这一重要事实得到了大量临床前模型和临床研究文献的支持。为了在药物筛选、开发和优化方面取得进展，对在体内时间和空间上测量肿瘤缺氧和血管生成的技术的需求日益增长。这在新兴的抗血管生成和抗缺氧治疗时代尤其有用。我们建议开发一种便携式、低功耗、低成本、准确可靠的多模态光学光谱系统，采用新型光纤探针，在小动物模型中动态表征肿瘤缺氧、血管生成、代谢以及组织药物浓度，而不存在操作员偏差。多模态光学光谱系统将是一台笔记本电脑或电池供电的控制台，集成了多个led、双通道光谱仪、光纤探头、电子设备和定制软件，可用于在体内执行漫反射和荧光光谱。光纤探头将包括一个干涉压力传感器，可用于控制探针组织压力，以可靠和可重复地进行组织光学特性的光谱测量。这项工作（第一阶段）的目标是：(1)使用led和干涉式光纤传感器设计核心技术，(2)表征其性能指标，(3)验证其在临床前乳腺肿瘤模型中的实用性。该技术将在二期STTR项目期间扩展到包括定量荧光测量，以及不同的探针设计，为异位（生长在侧面的肿瘤）和正位模型的实施提供灵活性。商业设备可以作为单模态（漫反射）或多模态（反射和荧光）设备销售。第一阶段的结果将导致第一代Quantilux设备的产品化，而多模态第二代设备正在完善中。二期及以后的总体目标将是开发一种可销售的设备，并验证其在小鼠肿瘤模型中纵向肿瘤治疗监测的实用性。

Angiogenesis and hypoxia can significantly influence the efficacy of therapy and the behavior of surviving tumor cells. This important fact is supported by a vast amount of literature on pre-clinical models and clinical studies. There is growing demand for technologies to measure tumor hypoxia and angiogenesis temporally and spatially in vivo to enable advances in drug screening, development and optimization. This is particularly useful in the emerging era of anti-angiogenesis and anti-hypoxia therapies. We propose to develop a portable, low power consumption and low-cost, yet accurate and reliable, multimodality optical spectroscopy system with a novel fiber-optic probe to dynamically characterize tumor hypoxia, angiogenesis, and metabolism as well as tissue drug concentration in small animal models without operator bias. The multimodality optical spectroscopy system will be a laptop or battery powered console with the integration of multiple LEDs, a dual-channel spectrometer, a fiber optic probe, electronics and custom software that can be used to perform both diffuse reflectance and fluorescence spectroscopy in vivo. The fiber-optic probe will include an interferometric pressure sensor that can be used to control the probe-tissue pressure for reliable and reproducible spectroscopic measurement of tissue optical properties. The aims of the proposed work (Phase I) will be to (1) design the core technology using LEDs and an interferometric fiber-optic sensor, (2) characterize its performance metrics and (3) validate its utility in a pre-clinical mammary tumor model. This technology will be extended to include quantitative fluorescence measurements in the Phase II STTR project period along with different probe designs to provide flexibility in implementation of this technology to ectopic (tumors grown on flank) and orthotopic models. The commercial device can be marketed as either a single- modality (diffuse reflectance) or a multi-modality (reflectance and fluorescence) device. The outcome of Phase I will lead to a 1st generation Quantilux device which can be productized while the multi-modality 2nd generation device is being refined.The overall objective in Phase II and beyond will be to develop a marketable version of the device and validate its utility for longitudinal tumor therapy monitoring in mouse tumor models.