Optical Dosimetry for Clinical Trials of Pc 4 Photodynamic Therapy

描述（由申请人提供）：PC 4是一种用于光动力疗法（PDT）的有前途的第二代光敏剂，目前正处于治疗皮肤T细胞淋巴瘤（CTCL）、基底细胞癌（BCC）和皮肤转移的临床试验阶段。其他临床试验正在凯斯西储大学的早期规划阶段。PC 4具有优异的生物物理特性，包括在670 nm处的强烈消光，其中光在组织中的穿透是有效的，以及高单线态氧量子产率。在国家癌症研究所的支持下，凯斯的研究人员已经广泛地描述了PC 4-PDT的生物学反应。NCI还赞助了所有临床前IND（研究性新药）指导的研究，并为临床试验提供GMP（良好生产规范）PC 4。因此，对PC 4进行了重大的科学和财政投资。I期试验的初步经验是积极的，但它也强调了迫切需要光学剂量测定和监测，以作出合理的治疗计划决定。PDT的结果取决于整个病变中敏化剂和光的可用性，并且PC 4-PDT的单线态氧机制需要氧。这些因素都不能假设，因此必须直接或间接测量。光动力剂量和/或生物响应的沉积的光学报告物也是期望的。在PC 4的特殊情况下，出现了特殊的问题和机会。例如，由于其在治疗波长处的极高消光，组织中的PC 4可能影响光的传输。为了解决这些与正在进行和计划中的临床试验密切相关的剂量测定和监测问题，我们提出了以下具体目标：（1）构建和表征能够在CTCL和BCC患者中提供PDT照射并执行荧光和反射光谱的光学系统;（2）评估照射诱导的PC 4荧光增加作为体内可能的剂量度量;（3）评价光散射作为报告线粒体的手段！体内对PC 4-PDT的反应;和（4）研究肿瘤内注射后PC 4的动力学和肿瘤内分布，并确定这种给药途径的功效。与公共卫生的相关性：目前正在测试光动力疗法用于治疗几种皮肤病。这里提出的研究将开发用于测量决定这种治疗结果的量的方法。结果将有助于正在进行的临床试验。

DESCRIPTION (provided by applicant): PC 4 is a promising second generation photosensitizer for photodynamic therapy (PDT) that is now in Phase clinical trials for the treatment of cutaneous T cell lymphoma (CTCL), basal cell carcinoma (BCC) and cutaneous metastases. Other clinical trials are in early planning stages at Case Western Reserve University. PC 4 has excellent photophysical characteristics, including an intense extinction at 670 nm, where light penetration in tissue is efficient, and high singlet oxygen quantum yield. Biological responses to PC 4-PDT have been extensively characterized by researchers at Case with support of the National Cancer Institute. NCI also sponsored all of the preclinical IND (Investigational New Drug)-directed studies and provides GMP (Good Manufacturing Practices) PC 4 for the clinical trials. Thus, there has been a significant scientific and financial investment in PC 4. Initial experience in the Phase I trial has been positive, however it has also underscored the urgent need for optical dosimetry and monitoring in order to make rational treatment planning decisions. The outcome of PDT depends on the availability of sensitizer and light throughout the lesion, and the singlet oxygen mechanism of PC 4-PDT requires oxygen. None of these ingredients can be assumed and must therefore be measured directly or indirectly. Optical reporters of the deposition of photodynamic dose and/or biological response are also desirable. Special problems and opportunities present themselves in the particular case of PC 4. For example, because of its extremely high extinction at the treatment wavelength, PC 4 in the tissue may influence the transport of light. To address these dosimetry and monitoring issues in close connection to ongoing and planned clinical trials, we propose the following specific aims: (1) to construct and characterize an optical system capable of delivering PDT irradiation and performing, both fluorescence and reflectance spectroscopy in CTCL and BCC patients; (2) to evaluate the irradiation-induced increase in PC 4 fluorescence as a possible dose metric in vivo; (3) to evaluate light scattering as a means of reporting mitochondria! responses to PC 4-PDT in vivo; and (4) to investigate the kinetics and intratumor distribution of PC 4 following intratumor injection and to establish the efficacy of this route of administration. Relevance to public health: Photodynamic therapy is being tested for the treatment of several cutaneous diseases. Research proposed here will develop means for measuring the quantities that determine the outcome of this therapy. Results will contribute to the ongoing clinical trials.