Photodynamic Therapy Mediated by Cerenkov Light Emitted from Radiopharmaceut

描述(申请人提供)：一些光介导性疗法，如光动力疗法(PDT)、光激活和光化学内化作用，已经并将继续被开发用于治疗癌症。光动力疗法已被用于或正在研究一系列人类肿瘤，但尽管其优点得到了充分的证明，但仍面临一些关键限制：1)肿瘤必须能够接触到外部光源。2)由于组织中光的不均匀和快速衰减，实现均匀和已知的剂量测量是一个重要的问题。3)由于光穿透的挑战，光敏剂仅限于那些合理吸收超过600 nm的光敏剂。4)只有发现的肿瘤才能被治疗--对转移疾病无效。最近，许多医用放射性核素通过切伦科夫效应发射光学光子的事实已被用于成像目的。这种发射的光在很大程度上倾向于光谱的紫外线和蓝色部分。此外，在核医学中，有广泛的肿瘤靶向放射性药物用于诊断和治疗，具有良好的肿瘤特异性。这开启了一种非常有趣的可能性，即利用靶向放射性药物产生的切伦科夫光作为“内部光源”来激活光疗法，如光动力疗法。如果可能，这将绕过上述PDT的许多光传递限制，因为光将在肿瘤细胞内发射，全身注射放射性药物可能导致原发肿瘤和转移性疾病的PDT。同时进行光动力疗法和放射性核素治疗也可能有协同作用。这项探索性的R21计划将使用体外和体内实验来评估切伦科夫激活的PDT在良好控制的条件下的可行性，并提供必要的数据，以确定在动物临床前试验中是否有价值追求这一有吸引力的概念。

DESCRIPTION (provided by applicant): A number of light-mediated therapies, such as photodynamic therapy (PDT), photoactivation and photochemical internalization have been, and are continuing to be, developed for treating cancer. Photodynamic therapy is used, or is under investigation, for a range of human tumors, but despite its well- documented strengths suffers a number of critical limitations: 1) The tumor has to be accessible to an external light source. 2) Achieving uniform and known dosimetry due to the uneven and rapid attenuation of light in tissue is a significant problem. 3) Photosensitizers are limited to those with reasonable absorption beyond 600 nm due to light penetration challenges. 4) Only detected tumors can be treated - ineffective against metastatic disease. Recently, the fact that many medical radionuclides emit optical photons via the Cerenkov effect has been exploited for imaging purposes. This emitted light is heavily weighted towards the ultraviolet and blue part of the spectrum. Furthermore, in nuclear medicine there are a wide range of tumor-targeted radiopharmaceuticals used both for diagnosis and at higher activity levels for therapy, that have good tumor specificity. This opens up the very interesting possibility of using the Cerenkov light generated from targeted radiopharmaceuticals as an "internal light source" to activate phototherapies such as PDT. If possible, this would circumvent many of the limitations of light delivery for PDT described above, as light would be emitted within the tumor cells, and the systemic injection of the radiopharmaceutical could potentially lead to PDT in both primary tumors and metastatic disease. There also may be synergistic effects of simultaneous PDT and radionuclide therapy. This exploratory R21 proposal will use in vitro and in vivo experiments to assess the feasibility of Cerenkov-activated PDT under well-controlled conditions and provide data that is necessary to determine if there is value in then pursuing this attractive concept in clinically-relevant preclinical trials in animals.