Functional Optical Coherence Tomography for Monitoring Drug Resistance in Cancer

描述(申请人提供)：分子信号转导是癌症的重要治疗靶点，分子治疗学已在治疗多种癌症方面取得了一定的成功。然而，我们对体内药效学效应的不完全了解限制了这些分子疗法的成功。我们最近发展了一种新的分子成像技术，光热光学相干层析成像(OCT)，它将高分辨率分子成像的穿透深度扩展到超过显微镜的极限。目前的提议将进一步开发用于细胞受体体内成像的光热OCT，并将这一新技术与多普勒OCT和高光谱成像的高分辨率血流动力学成像能力相结合，以全面了解分子癌症治疗在小鼠窗舱中生长为肿瘤的人类细胞中的药效学效应。第一个目标是使用组合的高光谱/OCT显微镜来量化血液氧合的变化，以及三维血流和微血管形态与肿瘤生长和抗血管生成治疗的关系。第二个目标是开发用于细胞受体体内成像的光热OCT，并将量化小鼠窗腔中受体抑制的药效学。最终目标将结合光热OCT和高光谱/多普勒OCT来量化小鼠窗腔肿瘤受体表达和联合受体抑制和抗血管生成治疗后血流动力学反应的纵向变化。这些研究将建立我们新的血流动力学(多普勒OCT和高光谱成像)和分子(光热OCT)成像技术，作为临床前应用的高分辨率、三维药物筛选方法。这项工作将在马克·德惠斯特博士和约瑟夫·伊扎特博士的共同指导下进行，他们是杜克大学肿瘤治疗和光学成像领域的专家。这种多学科的环境将为专业成长和科学进步提供绝佳的机会。 公共卫生相关性：这项工作将开发成像方法，在临床前模型中研究药物的血流动力学和分子反应，从而制定合理的剂量和调度策略，使这些药物的效果最大化。在这项提议中开发的光学成像方法很有吸引力，因为它提供了一套独特的多功能信息，这是其他技术难以获得的；它价格低廉，很容易在广泛的学科中应用。未来，类似的技术可以转化为临床使用，为包括癌症、阿尔茨海默氏症和神经疾病在内的各种疾病的患者提供个性化护理，从而降低发病率和死亡率。

DESCRIPTION (provided by applicant): Abstract Molecular signaling is a critical therapeutic target in cancer, and molecular therapeutics have achieved some success in treating a variety of cancers. However, our incomplete knowledge of pharmacodynamic effects in vivo limits the success of these molecular therapies. We have recently developed a new molecular imaging technique, photothermal optical coherence tomography (OCT) that extends the penetration depth of high resolution molecular imaging beyond the microscopy limit. The current proposal will further develop photothermal OCT for in vivo imaging of cell receptors, and will combine this new technique with the high resolution hemodynamic imaging capabilities of Doppler OCT and hyperspectral imaging to provide a comprehensive picture of the pharmacodynamic effects of molecular cancer therapies in human cells grown into tumors in the mouse window chamber. The first aim will use a combined hyperspectral / OCT microscope to quantify changes in blood oxygenation, and three dimensional blood flow and microvessel morphology with tumor growth and with antiangiogenic treatment. The second aim will develop photothermal OCT for in vivo imaging of cell receptors, and will quantify the pharmocodynamics of receptor inhibition in the mouse window chamber. The final aim will combine photothermal OCT and hyperspectral / Doppler OCT to quantify longitudinal changes in both receptor expression and hemodyanmic response to combined receptor inhibition and antiangiogenic therapies in mouse window chamber tumors. These studies will establish our novel hemodynamic (Doppler OCT and hyperspectral imaging) and molecular (photothermal OCT) imaging techniques as high resolution, three-dimensional drug screening methods for preclinical applications. This work will be conducted under the co-mentorship of Drs. Mark Dewhirst and Joseph Izatt, who are experts in the fields of tumor therapy and optical imaging, respectfully, at Duke University. This multi-disciplinary environment will provide an excellent opportunity for professional growth and scientific advancement. PUBLIC HEALTH RELEVANCE: This work will develop imaging methods to study the hemodynamic and molecular response to drugs in preclinical models, allowing for the formulation of rational dosing and scheduling strategies that maximize the effect of these drugs. The optical imaging approach developed in this proposal is attractive because it provides a unique set of multi-functional information that is difficult to obtain with other techniques; it is cheap and readily applied across a broad range of disciplines. In the future, similar technologies could be translated to clinical use to provide individualized care to patients with a variety of diseases including cancer, Alzheimer's, and neural diseases, thus decreasing morbidity and mortality.