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

 描述(申请人提供)：肿瘤缺氧是实体瘤的一个重要特征，也是治疗反应的调节器。由于氧气从血管扩散到100-150m，快速生长的肿瘤通常有两个缺氧区：位于肿瘤中心的慢性缺氧区和扩散距离内的循环(或急性)缺氧区。大量研究发现，缺氧，特别是其短暂的波动，会导致肿瘤转移增加，并对放射和药物产生抵抗力。通过增加氧气的输送和减少肿瘤内的氧气消耗来减少缺氧的策略正在探索中，以克服缺氧诱导的辐射和药物耐药性。因此，对在体内非侵入性测量肿瘤氧合的技术的需求日益增长，以促进药物筛选、开发和优化方面的进展。然而，慢性缺氧和循环性缺氧(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。我们最近开发了侧射光纤传感器和第一代(Gen-1)频域近红外光谱(FD-NIRS)，用于量化模型肿瘤的组织氧合和总血红蛋白含量。这种扁平传感器可以方便可靠地附着在肿瘤表面，是啮齿动物肿瘤模型的纵向监测和体内抗缺氧药物研究的理想工具。该项目的目标是开发第二代(GEN-2)FD-NIRS仪器，提高速度和吞吐量，并验证其用于纵向评估肿瘤缺氧和放化疗的疗效。我们假设：1)不同乳腺肿瘤的缺氧时间分布不同；2)双胍类药物(如二甲双胍或苯福明)可降低乳腺癌细胞的氧耗，从而提高其放射敏感性。将通过以下具体目标来验证这些假设：(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)在乳腺癌原位模型中量化肿瘤缺氧的特征；以及(3) 目的：使用GEN-2装置评价二甲双胍和放射治疗乳腺癌原位模型的疗效。我们的长期目标是开发一种便携式/可穿戴、低成本的FD-NIRS设备，以帮助开发和优化抗缺氧药物和放化疗。AIMS的成功完成不仅将产生关于肿瘤缺氧的新知识，为后续临床研究进一步阐明缺氧在癌症治疗中的作用奠定基础，而且将加强阿克伦大学的生物光子学研究和教育。

 DESCRIPTION (provided by applicant): 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 The University of Akron.