Optimizing cancer photodynamic therapy using photoacoustic lifetime imaging

描述(申请人提供)：头颈部癌症每年占美国所有新发癌症的3.2%(39750人)，占所有癌症死亡人数的2.2%(12460人)。其中约45%的患者在接受手术和放疗以及化疗或不化疗的初级治疗后会复发。以前接受过化疗的患者的复发往往更具侵袭性，一项研究报告了中位生存期为107天。在这项建议中，我们解决了迫切需要一种微创、无毒、成本效益高的局部治疗方法来治疗复发的头颈癌，并将与治疗相关的发病率降至最低，这将使患者在其余生中尽可能正常地发挥作用。我们相信 这可以通过光动力疗法(PDT)和光声寿命成像(PALi)相结合来实现，光声寿命成像是一种新开发的组织氧成像技术。光动力疗法是一种光激活的局部癌症治疗方法。在过去的20年里，广泛的研究已经证实光动力疗法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光动力疗法的疗效。我们假设，使用PALI测量组织氧的能力，并提高其在肿瘤环境中的水平将改善治疗，其结果和治愈率。此外，PALI图像将提供对光穿透到治疗部位的实时评估，以及个性化优化PDT光剂量的可能性。这份R01提案是基于一个正在进行的R21项目的结果，该项目显示了在小动物身上成像组织氧的可行性。我们将首先对PALI技术进行全面的调查，以便准确地描述其在环境参数方面的精确度和适用范围(目标1)。将在小动物身上测试PALI在活体环境中的应用范围(目标2)。根据实验结果，我们将开发一种便携式临床系统，用于PALI引导的PDT治疗(目标3)。该系统将在大型动物头颈部癌症模型中进行评估。然后将进行更广泛的研究，以检验Pali反馈可以指导参数修改(包括混合气体呼吸和光剂量)的假设，以优化PDT治疗的疗效(目标4)。最终，我们预计这项技术将转化为临床，显著改善头颈部癌症患者的治疗结果。该项目的结果还可能推动PALI的开发，用于其他临床应用，如指导化疗和放射治疗。

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.