Fluorescence Imaging to Optimize Cancer Therapy

描述(由申请人提供)： 光学方法用于癌症成像和治疗的使用正在迅速增长，这在很大程度上是因为它们在早期检测方法的设置、癌症前期的治疗或作为辅助治疗方面效果良好。光学活性物质可以在肿瘤中提供分子特异性或部位特异性定位，在这项工作中，我们利用这两种方法进行诊断和治疗。特别是，我们专注于氨基酮丙酸，它诱导细胞线粒体中原卟啉IX(PPIX)的产生，从而提供了一种细胞新陈代谢的诊断指标以及一种战略性地在该部位造成光动力损害的方法。我们将使用两种技术先进的方法来量化体内的荧光，包括我们的组织微采样探头和我们的近红外断层成像仪器。我们将系统地研究测量肿瘤中PPIX的荧光的最佳方法，使用针头测量、扩散探针测量和组织的扩散断层成像。我们将在几个具体的生物学假设中使用最优解。首先，在诊断应用中，我们将研究PPIX的产生如何与癌细胞的生长速度有关，重点放在邓宁前列腺癌中可用的多个细胞系。这也将有助于探索在成像中使用重复剂量的可行性，并检查这如何影响测量。在治疗靶向方面，我们将使用成像系统来帮助我们探索我们开发的一种新的靶向方法，该方法将光动力预治疗与放射治疗协同结合。我们已经发现，线粒体的损伤会导致急性呼吸停止，从而减少氧气的消耗，并为提高肿瘤的氧合提供了一个很好的方法。这种效应与单剂量放射治疗相结合，被发现可以增加肿瘤破坏的效果。在这项研究中，我们将进一步研究这种影响，重点是开发这两种疗法分次递送的潜力。由于ALA-PPIX提供了细胞代谢率的比例测量，我们将使用PPIX的荧光作为细胞活动的诊断测量，而使用吲哚青绿荧光作为组织血管体积的测量。通过对光信号进行适当的过滤和排序，可以在同一组织中对两者进行量化，这种联合成像方法将被用于检测体内血管和细胞损伤的可靠性。

DESCRIPTION (provided by applicant): The use of optical methods for imaging and treatment of cancer is growing rapidly, largely because they work well in the setting of early detection methods, treatment of pre-malignancies or as an adjuvant treatment. Optically active agents can provide a molecular-specific or site-specific localization in tumors, and in this work we exploit both of these for diagnostic and therapeutic use. In particular, we focus on aminolevulinic acid, which induces production of protoporphyrin IX (PPIX) in the mitochondria of cells, thereby providing both a diagnostic measure of cellular metabolism as well as a way to strategically cause photodynamic damage at this site. We will use two technologically advanced approaches to quantifying the fluorescence in vivo, including our tissue micro-sampling probe and our near-infrared tomographic instrumentation. We will systematically examine the optimal way to measure fluorescence from PPIX in tumors, using needle measurements, diffuse probe measurements and diffuse tomography imaging of tissue. We will use the optimal solution in several specific biological hypotheses. First in diagnostic use, we will examine how the production of PPIX is related to the growth rate of cancer cells, focusing on the multiple cell lines available in the Dunning prostate tumor. This will also help to explore the feasibility of using repeated dosing in imaging, and examining how this affects the measurements. For therapeutic targeting, we will use the imaging system to help us explore a novel targeting approach that we have developed, which synergistically combines photodynamic pre-treatment with radiation therapy. We have found that damage to the mitochondria causes acute respiration shut down, reducing the consumption of oxygen and providing a good way to increase the oxygenation in tumors. This effect was combined with single dose radiation therapy and was found to increase the efficacy of tumor destruction. In this study, we will further examine this effect focusing on exploiting the potential for fractionated delivery of both therapies. Since ALA-PPIX provides a proportionate measure of the cellular metabolic rate, we will use the fluorescence from PPIX as a diagnostic measure of cellular activity, while using indocyanine green fluorescence as a measure of the vascular volume of the tissue. Both can be quantified in the same tissue by appropriate filtering and sequencing of the light signals, and this combined imaging approach will be examined for reliability of monitoring vascular versus cellular damage in vivo.