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

使用近红外光谱对体内肿瘤缺氧进行纵向评估

• 批准号: 9415230
• 负责人: Bing Yu
• 金额: $ 39.91万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-11 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415230
• 关键词: Longitudinal; Assessment; Tumor; Hypoxia; vivo

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.

肿瘤缺氧是实体瘤的重要特征，也是治疗反应的调节因素。因为 氧气从血管扩散100-150μm，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内的循环（或急性）缺氧区域 距离。大量研究发现缺氧，尤其是其时间波动，会导致肿瘤的增强 转移以及对辐射和药物的抵抗力。通过增加氧气输送来减少缺氧的策略 和减少肿瘤内的耗氧量都在探索，以克服缺氧引起的 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 体内暂时测量肿瘤氧合，以促进药物筛选、开发和 优化。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，主要是因为缺乏连续的非侵入性工具 量化体内肿瘤缺氧的时间分布。我们最近开发了一种侧面发射光纤传感器 以及用于组织定量的第一代 (GEN-1) 频域近红外光谱 (FD-NIRS) 模型肿瘤中的氧合和总血红蛋白含量。扁平传感器可以轻松可靠地安装 到肿瘤表面，因此是纵向监测啮齿动物肿瘤模型和研究抗肿瘤药物的理想工具 体内缺氧药物。 拟议项目的目标是开发具有改进功能的第二代 (GEN-2) FD-NIRS 仪器 速度和吞吐量，并验证其用于肿瘤缺氧的纵向评估和疗效 放化疗。我们假设 1）不同乳腺肿瘤的缺氧时间分布有所不同，并且 2）双胍类药物（例如二甲双胍或苯乙双胍）可以减少乳腺癌细胞的耗氧量， 从而提高其放射敏感性。将通过以下具体目标来检验假设：（1） 构建第二代 FD-NIRS 仪器，速度提高 10 倍，吞吐量提高 15 dB； (2) 量化 乳腺癌原位模型肿瘤缺氧的特点； (3) 评估二甲双胍的疗效 以及使用 GEN-2 装置对乳腺癌原位模型进行照射。我们的长期目标是发展 便携式/可穿戴式低成本 FD-NIRS 设备，有助于开发和优化抗缺氧技术 药物和放化疗。目标的成功完成不仅会产生新的知识 关于肿瘤缺氧的研究，为后续临床研究进一步阐明缺氧的作用奠定基础 在癌症治疗方面，还将加强马凯特大学的生物光子学研究和教育。