Optical Dosimetry for Clinical Trials of Pc 4 Photodynamic Therapy

描述(申请人提供)：PC4是一种很有前途的第二代光动力疗法(PDT)光敏剂，目前正处于临床试验阶段，用于治疗皮肤T细胞淋巴瘤(CTCL)、基底细胞癌(BCC)和皮肤转移。凯斯西储大学的其他临床试验正处于早期规划阶段。PC4具有优良的光物理特性，包括在670 nm处的强消光，光在组织中的穿透是有效的，以及高的单线态氧量子产率。在国家癌症研究所的支持下，凯斯大学的研究人员对PC 4-PDT的生物学反应进行了广泛的表征。NCI还赞助了所有由IND(研究新药)指导的临床前研究，并为临床试验提供GMP(良好制造实践)PC 4。因此，对PC 4进行了大量的科学和财政投资。第一阶段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，以做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线的可用性，而PC4-PDT的单线态氧机制需要氧气。所有这些因素都不能假设，因此必须直接或间接衡量。光动力剂量和/或生物响应的沉积的光学记录器也是理想的。在PC4的特殊情况下，存在着特殊的问题和机会。例如，由于其在治疗波长下的极高消光率，组织中的PC4可能会影响光的传输。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学和监测问题，我们提出了以下具体目标：(1)构建和表征能够提供PDT照射的光学系统，并在CTCL和BCC患者中进行荧光和反射光谱；(2)评估辐射诱导的PC-4荧光增加作为体内可能的剂量度量；(3)评估光散射作为报告线粒体的一种手段！研究PC-4-PDT在体内的反应；(4)研究PC-4在瘤内注射后的动力学和瘤内分布，并建立这种给药途径的疗效。与公众健康相关：光动力疗法正在测试中，用于治疗几种皮肤病。这里提出的研究将开发出测量决定这种疗法结果的数量的方法。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.