Quantitative Evaluation of Cerenkov Luminescence for Imaging and Therapy

描述(申请人提供)：切伦科夫辐射是一种现象，当带电粒子在组织等介质中的运动速度快于光速时，就会发射光学光子。最近，我们和其他人发现，由于切伦科夫效应，在给小动物注射释放的放射性核素后，体内会产生可测量的可见光。此外，产生可检测信号所需的注入活度与小动物分子成像应用是一致的。这一观察导致了一种名为切伦科夫发光成像(CLI)的新的混合分子成像方式的发展，这种成像方式允许使用灵敏的电荷耦合器件(CCD)相机在活体内成像标记有？发射的放射性核素的生物分子的空间分布。这对于使用重要的治疗性放射性核素(如90Y)进行临床前研究特别有价值，这些放射性核素在示踪剂量下不能使用任何其他体内成像技术进行成像。CLI还提供了一种快速、低成本、易于获取的方法来对小动物体内的PET放射性示踪剂进行成像。切伦科夫发光的翻译机会也存在。CLI可能适用于皮肤、眼睛和口腔，也可以在体内使用内窥镜或导管设备。正在探索的另一个可能的应用是使用放射性示踪剂产生的丰富的蓝/UV切伦科夫光作为组织内部深处光激活的内部光传递源，例如在光动力疗法和光激活药物传递中。这项建议的目标是提供对切伦科夫发光应用于生物医学应用的定量了解，并产生数据，作为指导分子成像和治疗界开发小动物和转译切伦科夫应用的平台。具体目标是通过计算/模拟、模体实验和活体研究相结合的方式，获得对切伦科夫信号和光谱的详细定量理解，这些信号和光谱可以从组织中测量。我们将比较两种不同摄像技术对微弱切伦科夫信号的检测性能，并确定检测极限。还将描述利用切伦科夫层析成像的光谱信息以及在涉及切伦科夫和生物发光信号的多模式研究中进行光谱混合的能力。最后，我们将估计放射性示踪剂通过切伦科夫效应传递到组织的光能，以确定这一机制是否可以用作光激活的内部激发源。这项工作的预期成果是详细了解系统管理的放射性示踪剂产生、分配和传输可见切伦科夫辐射的情况，这将成为根据这一新观察到的现象开发生物医学应用的关键基础。 与公共卫生相关：最近观察到，通常用于核医学医学成像检查的放射性示踪剂通过切伦科夫效应发出可检测到的可见光。这为使用灵敏的光学成像相机对诊断和治疗放射性核素进行活体成像开辟了新的机会，特别是在临床前小动物研究中。使用这种切伦科夫辐射来帮助在不使用外部激光的情况下在体内深处提供光激活疗法也是有前景的。这项建议中的研究试图确定切伦科夫光用于成像和治疗应用的可行性。

DESCRIPTION (provided by applicant): Cerenkov radiation is a phenomenon in which optical photons are emitted when a charged particle moves faster than the speed of light in a dielectric medium such as tissue. Recently we, and others, have discovered that measurable visible light due to the Cerenkov effect is produced in vivo following administration of ?-emitting radionuclides to small animals. Furthermore, the amounts of injected activity required to produce a detectable signal are consistent with small animal molecular imaging applications. This observation has led to the development of a new hybrid molecular imaging modality known as Cerenkov luminescence imaging (CLI) that allows the spatial distribution of biomolecules labeled with ?-emitting radionuclides to be imaged in vivo using sensitive charge-coupled device (CCD) cameras. This is especially valuable for preclinical studies with important therapeutic ?-emitting radionuclides, such as 90Y, that cannot readily be imaged at tracer doses using any other in vivo imaging technique. CLI also provides a fast, low-cost, readily accessible approach to image PET radiotracers in small animals. Translational opportunities for Cerenkov luminescence also exist. CLI might be possible for skin, eye and oral cavity, or using endoscopic or catheter-based devices inside the body. Another possible application that is being explored is to use the abundant blue/UV Cerenkov light produced by radiotracers as a source of internal light delivery deep inside tissues for photoactivation, for example in photodynamic therapy and photoactivated drug delivery. The goal of this proposal is to provide a quantitative understanding of Cerenkov luminescence as it applies to biomedical applications and to produce data that serves as a platform for guiding the development of small-animal and translational Cerenkov applications by the molecular imaging and therapeutics community. The specific aims address obtaining a detailed quantitative understanding of Cerenkov signals and spectra that can be measured from tissues through a combination of computation/simulation, phantom experiments and in vivo studies. We will compare the performance of two different camera technologies for the detection of weak Cerenkov signals, and determine detection limits. The ability to exploit spectral information for Cerenkov tomography, and for spectral unmixing in multimodal studies that involve both Cerenkov and bioluminescence signals, also will be characterized. Finally, we will estimate the light energy delivered to tissues by radiotracers via the Cerenkov effect, to determine if this mechanism can feasibly be used as a source of internal excitation for photoactivation. The anticipated outcome of this work is a detailed understanding of the production, distribution and transport of visible Cerenkov radiation by systemically-administered radiotracers, that will serve as a critical foundation on which to develop biomedical applications based on this newly-observed phenomenon. PUBLIC HEALTH RELEVANCE: Radiotracers commonly administered for medical imaging examinations in nuclear medicine have recently been observed to emit detectable amounts of visible light via the Cerenkov effect. This opens up new opportunities for in vivo imaging of diagnostic and therapeutic radionuclides using sensitive optical imaging cameras, especially in preclinical small-animal studies. There also are prospects for using this Cerenkov radiation to assist in delivering light-activated therapies deep inside the body without the use of an external laser. This research in this proposal seeks to determine the feasibility of using Cerenkov light fo both imaging and therapeutic applications.