Photodynamic Therapy Mediated by Cerenkov Light Emitted from Radiopharmaceut

描述（由申请人提供）：许多光介导的疗法，如光动力疗法（PDT）、光活化和光化学内化，已经并将继续开发用于治疗癌症。光动力学疗法被用于或正在研究用于一系列人类肿瘤，但是尽管其有据可查的优势，但仍受到许多关键限制：1）肿瘤必须可接近外部光源。2)由于光在组织中的不均匀和快速衰减，实现均匀和已知的剂量测定是一个重要的问题。3)由于光穿透的挑战，光敏剂仅限于具有超过600 nm的合理吸收的那些。4)只有检测到的肿瘤可以治疗-对转移性疾病无效。最近，许多医学放射性核素通过切伦科夫效应发射光子的事实已经被用于成像目的。这种发射的光严重偏向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以更高的活性水平用于治疗，具有良好的肿瘤特异性。这开辟了一个非常有趣的可能性，即使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PDT。如果可能的话，这将规避上述PDT的光递送的许多限制，因为光将在肿瘤细胞内发射，并且放射性药物的全身注射可能潜在地导致原发性肿瘤和转移性疾病中的PDT。同时PDT和放射性核素治疗也可能有协同作用。这项探索性的R21提案将使用体外和体内实验来评估在良好控制条件下Cerenkov激活的PDT的可行性，并提供必要的数据，以确定在动物临床相关的临床前试验中追求这一有吸引力的概念是否有价值。

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.