Longitudinal Assessment of Tumor Hypoxia in vivo Using Near-Infrared Spectroscopy

肿瘤缺氧是实体瘤的重要特征，也是治疗反应的调节因子。因为 氧气从血管扩散到100-150m，快速生长的肿瘤通常有两个缺氧区：a 肿瘤中心的慢性缺氧区和扩散内的循环(或急性)缺氧区 距离。许多研究发现，缺氧，特别是其短暂的波动，会导致肿瘤增强。 转移以及对辐射和药物的抵抗。通过增加氧气输送来减少缺氧的策略 和降低肿瘤内的氧气消耗都是为了克服缺氧引起的 对辐射和药物的抵抗力。因此，对非侵入性技术的需求不断增长 在体内暂时测量肿瘤的氧合，以促进药物筛选、开发和治疗的进展 优化。然而，慢性低氧和循环低氧(CH)的相对贡献以及 治疗反应很难确定，主要是因为缺乏一种非侵入性的工具来持续 量化体内肿瘤缺氧的时间分布。我们最近开发了一种侧射光纤传感器。 和用于组织定量的第一代(Gen-1)频域近红外光谱(FD-NIRS) 模型肿瘤的氧合作用和总血红蛋白含量。平板传感器可轻松可靠地安装 是啮齿动物肿瘤模型纵向监测和抗肿瘤研究的理想工具。 体内缺氧药物。 拟议项目的目标是开发第二代(Gen-2)FD-NIRS仪器，该仪器具有改进的 速度和吞吐量，并验证它用于纵向评估肿瘤缺氧和 放化疗。我们假设1)缺氧的时间分布在不同的乳腺肿瘤和 2)双胍类药物(如二甲双胍或苯双胍)可降低乳腺癌细胞的耗氧量， 从而提高它们的辐射敏感性。将进行以下具体目标来检验假设：(1) 构建速度为10倍、吞吐量提高15分贝的第二代FD-NIRS仪器；(2)量化 原位乳腺癌模型中肿瘤缺氧的特点；(3)评价二甲双胍的疗效 以及使用GEN-2设备对乳腺癌原位模型进行放射治疗。我们的长远目标是发展 便携式/可穿戴、低成本的FD-NIRS设备，可帮助开发和优化抗缺氧 药物和放化疗。这些目标的成功完成不仅将产生新的知识 为后续临床研究进一步阐明肿瘤缺氧的作用奠定了基础 在癌症治疗方面，也将加强马奎特大学的生物光子学研究和教育。

Tumor hypoxia is an important characteristic of solid tumors and a modulator of therapeutic response. Because oxygen diffuses 100-150 m from blood vessels, fast growing tumors often have two hypoxic regions: a chronically hypoxic region in the center of the tumor and a cycling (or acute) hypoxic region within the diffusion distance. Numerous studies have found that hypoxia, especially its temporal fluctuation, leads to enhanced tumor metastasis and resistance to radiation and drugs. Strategies to reduce hypoxia by increasing delivery of oxygen and decreasing oxygen consumption within the tumor are both being explored to overcome hypoxia-induced resistance to radiation and drugs. Therefore, there is growing demand for technologies that noninvasively measure tumor oxygenation temporally in vivo to enable advances in drug screening, development and optimization. However, the relative contributions of chronic hypoxia and cycling hypoxia (CH) as well as the therapeutic responses are difficult to determine primarily due to the lack of a noninvasive tool to continuously quantify the temporal profile of tumor hypoxia in vivo. We have recently developed a side-firing fiber optic sensor and a 1st generation (GEN-1) frequency-domain near-infrared spectroscopy (FD-NIRS) for quantification of tissue oxygenation and total hemoglobin content in model tumors. The flat sensor can be easily and reliably attached to a tumor surface and thus is an ideal tool for longitudinal monitoring of rodent tumor models and studying anti- hypoxia drugs in vivo. The objective of the proposed project is to develop a 2nd generation (GEN-2) FD-NIRS instrument with improved speed and throughputs and validate it for longitudinal assessment of tumor hypoxia and the efficacy of chemoradiotherapy. We hypothesize that 1) the temporal profiles of hypoxia vary in different breast tumors and 2) biguanide drugs (e.g., metformin or phenformin) can reduce the oxygen consumption of breast cancer cells, thus improving their radiosensitivity. The following specific aims will be conducted to test the hypotheses: (1) to construct a 2nd generation FD-NIRS instrument with 10x speed and 15-dB better throughputs; (2) to quantify the characteristics of tumor hypoxia in orthotopic models of breast cancer; and (3) to assess the efficacy of metformin and irradiation in orthotopic models of breast cancer using the GEN-2 device. Our long-term goal is to develop a portable/wearable, low-cost FD-NIRS device that can aid in development and optimization of anti-hypoxia drugs and chemoradiotherapy. The successful completion of the aims will not only generate new knowledge about tumor hypoxia and lay the foundation for subsequent clinical studies to further delineate the role of hypoxia in cancer therapy, but also will enhance the biophotonics research and education at Marquette University.