NSF/FDA SIR: Assessing the Photocytotoxicity and Photochemistry of New Emerging Fluorophores

荧光成像是一种流行的生物医学工具，用于基础科学和临床实践，如疾病诊断和手术。荧光成像中使用的试剂可能表现出一定程度的光毒性（由于光的损害）。近年来，美国食品和药物管理局审查的荧光成像产品越来越多，光毒性问题引起了人们的极大兴趣。缺乏关于荧光剂光毒性主题的已建立的、经过充分验证的测试方法和科学专业知识，可能会导致具有潜在毒性的产品被清除，或者相反，与申办者在测试良性试剂方面进行过多的重复，导致产品上市的不必要延迟。因此，这个为期一年的NSF/FDR驻校学者项目的目标是建立标准化方法，用于评估活细胞中新兴荧光成像产品的光毒性。通过适当的传播和整合所获得的知识，该项目将能够大大提高安全有效的荧光成像产品及时转化为临床应用的可能性。 计划中的研究将与教育，指导和推广活动无缝集成，以推进生物光子学和监管科学领域的跨学科计划。研究结果将通过FDA和UMD联合举办的期刊出版物、会议和研讨会广泛传播。这项工作将在生物医学光学、分子成像和光生物学会议上发表。研究结果将提交给器械和放射卫生中心（CDRH）的监管审查人员，以做出知情的监管决策。本项目的总体目的是生成知识和测试工具，作为改进新兴荧光成像组合产品中光细胞毒性监管评价的基础。该项目的动机是需要在药物评价和研究中心（CDER）和器械和放射卫生中心（CDRH）审查的新兴“组合产品”中进行标准化的安全测试方法，以及对影响荧光剂安全性的因素有更好的科学理解。 该项目将系统地表征细胞系统中已建立和新出现的荧光团的光敏特性。 生物效应将与基本的光化学和物理参数相关联，以充分了解光敏化的机制。 研究旨在实现两个研究目标：（1）使用3 T3神经红更新（NRU）和其他测试量化已建立和新出现的荧光团的光细胞毒性，以及（2）建立标准化的最佳实践来评估荧光团的光毒性。该项目的主要成果将是一组测试方法-标准化测定，数据采集和处理的协议-代表评估细胞中新兴荧光成像剂光毒性的最佳实践。此外，生物效应将与基本的光化学和生物物理参数相关联，以充分了解光敏化的机制。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Fluorescence imaging is a popular biomedical tool used in basic science and clinical practice such as disease diagnosis and surgery. The agents used in fluorescence imaging can exhibit some degree of phototoxicity (damage due to light). In recent years, there has been an increasing number of fluorescence imaging products reviewed by the U.S. Food and Drug Administration, and the issue of phototoxicity is of significant interest. The lack of established, well-validated test methodologies and scientific expertise on the topic of fluorescent agent phototoxicity risks the clearance of products with toxic potential, or conversely, excessive iteration with sponsors on testing of benign agents, leading to unnecessary delays in product marketing. Therefore, the goal of this one-year NSF/FDR Scholar in Residence project is to establish standardized methods for evaluating phototoxicity of emerging fluorescence imaging products in living cells. Through proper dissemination and incorporation of gained knowledge, the project will be able to vastly improve the likelihood that safe and effective fluorescence imaging products are translated into clinical use in a timely manner. The planned research will be seamlessly integrated with educational, mentoring, and outreach activities to advance the cross-disciplinary program in the field of biophotonics and regulatory science. The results will be disseminated broadly through journal publications, conferences, and workshops held jointly at FDA and UMD. This work will be presented at conferences on biomedical optics, molecular imaging, and photobiology. The findings will be presented to regulatory reviewers in Center for Devices and Radiological Health (CDRH) to make informed regulatory decisions.The overall purpose of this project is to generate knowledge and testing tools as a foundation for improving regulatory evaluation of photo-cytotoxicity in emerging fluorescence imaging combination products. The project is motivated by the need for standardized safety test methods in the emerging "combination product" reviewed in the Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH), and a better scientific understanding of factors influencing fluorescent agent safety. The project will systematically characterize the photosensitizing properties of established and emerging fluorophores in cell-based systems. Biologic effects will be correlated with basic photochemical and photophysical parameters to fully understand the mechanisms underlying the photosensitization. Studies are designed to achieve two research objectives: (1) quantify photo-cytotoxicity of established and emerging fluorophores using 3T3 Neural Red Update (NRU) and other testings and (2) establish standardized best practices for evaluating the phototoxicity of fluorophores. The primary outcomes of this project will be a battery of test methods – protocols for standardized assaying, data acquisition, and processing – that represent best practices for evaluating the phototoxicity of emerging fluorescence imaging agents in cells. Additionally, biologic effects will be correlated with basic photochemical and photophysical parameters to fully understand the mechanisms underlying the photosensitization.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.