Optimizing cancer photodynamic therapy using photoacoustic lifetime imaging

描述（由申请人提供）：在美国，头颈癌每年占所有新发癌症的3.2%（39，750例），占所有癌症死亡的2.2%（12，460例）。这些患者中约45%在接受手术和放疗（伴或不伴化疗）的主要治疗后会复发。以前接受过化疗的患者的复发往往更具侵略性，一项研究报告的中位生存期为107天。在这项提案中，我们解决了迫切需要一种微创，无毒，具有成本效益的局部方式来治疗复发性头颈癌，并使治疗相关的发病率最低，这将使患者在其剩余的生命中尽可能正常地发挥作用。我们认为 这可以通过将光动力疗法（PDT）与光声寿命成像（帕利）结合来实现，光声寿命成像是一种新开发的用于组织氧成像的技术。PDT是一种光激活的局部癌症治疗方法。在过去的20年中，广泛的研究已经确定PDT在头颈部癌症的治疗中是有效的。然而，组织氧合和光穿透强烈影响PDT的功效。我们假设，使用帕利测量组织氧的能力，并增加其在肿瘤环境中的水平将改善治疗，其结果和治愈率。此外，帕利图像将提供对治疗部位的光穿透的实时评估以及PDT光剂量的个性化优化的可能性。该R01提案基于正在进行的R21项目的结果，该项目显示了小动物组织氧成像的可行性。我们将首先对帕利技术进行全面的调查，以准确地描述其精度和适用范围，如pH值和温度（目标1）等环境参数。帕利在体内环境中的应用范围将在小动物身上进行测试（目标2）。基于实验结果，我们将开发一种便携式临床系统，用于帕利引导的PDT治疗（目标3）。该系统将在大型动物头颈癌模型中进行评估。然后将进行更广泛的研究，以检验帕利反馈可以在个案基础上指导参数修改（包括气体混合物呼吸和光剂量）的假设，以优化PDT治疗的疗效（目标4）。最终，我们希望该技术能够应用于临床，显著改善头颈癌患者的治疗效果。该项目的结果还可以推动帕利在其他临床应用中的发展，例如指导化疗和放疗。

DESCRIPTION (provided by applicant): Head and neck cancers annually account for 3.2% (39,750) of all new cancers and 2.2% (12,460) of all cancer deaths in the US. Approximately 45% of these patients will relapse after primary therapy with surgery and radiation with or without chemotherapy. Recurrences in patients who previously received chemotherapy tend to be more aggressive, with one study reporting a median survival of 107 days. In this proposal we address the urgent need for a minimally invasive, non-toxic, cost-effective, local modality for treating recurrent head and neck cancers with minimal treatment-associated morbidity, which will allow the patient to function as normally as possible in their remaining life-time. We believe this can be achieved by combining Photodynamic therapy (PDT) with photoacoustic lifetime imaging (PALI), a newly developed technique for tissue oxygen imaging. PDT is a light-activated local cancer treatment. Extensive studies during the last 2 decades have established PDT as effective in the treatment of head and neck cancers. However, tissue oxygenation and light penetration strongly affect the efficacy of PDT. We hypothesize that the ability to measure tissue oxygen using PALI, and augmenting its level in the tumor environment will improve the treatment, its outcome and cure rates. Moreover, PALI images will provide a real-time assessment of light penetration to the treated site and the possibility of personalized optimization of PDT light dose. This R01 proposal is based on the results of an on-going R21 project that show feasibility of imaging tissue oxygen in small animals. We will first conduct a comprehensive investigation of the PALI technique in order to accurately characterize its precision and regions of applicability with respect to environmental parameters such as pH and temperature (Aim 1). The scope of the PALI application in an in vivo environment will be tested on small animals (Aim 2). Based on the experimental outcomes, we will develop a portable clinical system for PALI guided PDT treatment (Aim 3). The system will be evaluated in large animal head and neck cancer models. A more extensive study will then be conducted to test the hypothesis that PALI feedback can guide parameter modification (including gas mixture breathing and light dose) on a case-by-case basis, to optimize the efficacy of PDT treatment (Aim 4). Ultimately, we expect the technique to be translated to clinics, significantly improving treatment outcomes of head and neck cancer patients. The results of this project could also drive the development of PALI for other clinical applications, such as guiding chemotherapy and radiotherapy.