Functional Optical Coherence Tomography for Monitoring Drug Resistance in Cancer

摘要分子信号是癌症治疗的重要靶点，分子疗法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。我们最近开发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显微镜之外。目前的提案将进一步发展光热OCT用于细胞受体的体内成像，并将这种新技术与多普勒OCT的高分辨率血流动力学成像能力和高光谱成像相结合，以提供分子癌症治疗在小鼠窗腔中长成肿瘤的人类细胞的药效学效应的全面图像。第一个目标将使用联合高光谱/ OCT显微镜来量化肿瘤生长和抗血管生成治疗时血液氧合、三维血流和微血管形态的变化。第二个目标是开发光热OCT用于细胞受体的体内成像，并将量化小鼠窗口室中受体抑制的药效学。最终目的是结合光热OCT和高光谱/多普勒OCT，量化小鼠窗室肿瘤中受体表达的纵向变化和联合受体抑制和抗血管生成治疗的血流动力学反应。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dr。杜克大学的Mark Dewhirst和Joseph Izatt，他们是肿瘤治疗和光学成像领域的专家。这个多学科的环境将为专业成长和科学进步提供极好的机会。

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.