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

 描述（由申请人提供）：肿瘤缺氧是实体瘤的重要特征，也是治疗反应的调节剂。由于氧气从血管扩散100-150 μ m，快速生长的肿瘤通常有两个缺氧区域：肿瘤中心的慢性缺氧区域和扩散距离内的循环（或急性）缺氧区域。大量研究发现，缺氧，尤其是缺氧的时间波动，可导致肿瘤转移增强，对放射和药物的抵抗增强。正在探索通过增加肿瘤内氧气的输送和减少氧气消耗来减少缺氧的策略，以克服缺氧诱导的对辐射和药物的抗性。因此，对在体内时间上非侵入性地测量肿瘤氧合的技术的需求日益增长，以实现药物筛选、开发和优化的进步。然而，慢性缺氧和循环缺氧（CH）的相对贡献以及治疗反应很难确定，主要是由于缺乏无创工具， 连续量化体内肿瘤缺氧的时间曲线。我们最近开发了一种侧射光纤传感器和第一代（GEN-1）频域近红外光谱（FD-NIRS），用于定量模型肿瘤中的组织氧合和总血红蛋白含量。该平板传感器可以简单可靠地附着在肿瘤表面，因此是纵向监测啮齿动物肿瘤模型和研究体内抗缺氧药物的理想工具。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，并验证其用于肿瘤缺氧和放化疗疗效的纵向评估。我们假设1）缺氧的时间分布在不同的乳腺肿瘤中不同，2）双胍类药物（例如，二甲双胍或苯丙氨酸）可以减少乳腺癌细胞的耗氧量，从而提高其放射敏感性。将进行以下具体目标以检验假设：（1）构建具有10倍速度和15 dB更高吞吐量的第二代FD-NIRS仪器;（2）量化乳腺癌原位模型中肿瘤缺氧的特征;以及（3） 使用GEN-2器械评估二甲双胍和放疗在乳腺癌原位模型中的疗效。我们的长期目标是开发一种便携/可穿戴、低成本的FD-NIRS设备，可以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有关肿瘤缺氧的新知识，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，而且还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.