Cerenkov-emission based nanosensors to detect biologic activities in vivo

描述（由申请人提供）：可激活的光学和磁共振造影剂已被设计用于感测和可视化体内分子活动。然而，尽管核成像灵敏度很高，但在感测生物活动方面受到很大限制 物理上无法“打开”或“关闭”放射性。为了填补这一空白，我们假设 切伦科夫发光成像与纳米粒子结合可用于创建基于放射性衰变的可激活纳米传感器。蓝色切伦科夫光是由颗粒放射性发射（例如正电子或电子）穿过组织而产生的。切伦科夫光允许使用高灵敏度相机对放射性示踪剂进行光学成像。根据我们之前证明的放射性示踪剂体内切伦科夫发光成像的结果，该应用的总体目标是感测相关的酶活性 使用放射性金属和修饰的纳米粒子在体内治疗癌症 在这个新的 R01 应用中，与癌症相关的内切蛋白酶调节不同纳米粒子和作为切伦科夫发射体的放射性金属之间的物理相互作用。我们的假设将根据我们实验室强有力的初步数据在三个特定目标上进行测试：在特定目标（1）中，我们将探索纳米颗粒的不同设计原理，以评估不同涂层和放射性金属对切伦科夫发射的影响；在Specific Aim (2)中，我们将使用Cerenkov成像技术感测体内特定内切蛋白酶（基质金属蛋白酶-2、组织蛋白酶B和尿激酶型纤溶酶原激活剂）的酶活性；在具体目标 (3) 中，目标是实施量化纳米传感器的激活以及酶活性的过程。这是基于切伦科夫成像与正电子发射断层扫描 (PET) 成像的结合。 PET 成像可以对肿瘤中的纳米传感器进行独立量化（使用特定摄取值 (SUV)），无论其当前的激活状态如何。我们提出了一种固有的方法来校正组织衰减并对信号和酶活性进行相对量化。我们相信，所提出的研究构成了分子成像的一个创新方向和范式转变，因为它允许利用放射性示踪剂和光学读出来感测酶活性，将 PET 和光学成像的独特灵敏度结合在一起。所提出的研究的贡献是显着的，因为它扩展了核成像的潜在应用。它为放射性示踪剂检测相关生物信号提供了一条全新的途径。这些纳米传感器最终可能会进入临床领域，例如术中成像。

DESCRIPTION (provided by applicant): Activatable optical and magnetic resonance contrast agents have been devised to sense and visualize molecular activity in vivo. However, though highly sensitive, nuclear imaging has been limited considerably in sensing biological activities by the physical inability to switch radioactivity "on" or "off". To fill this gap, we hypothesize that Cerenkov luminescence imaging in conjunction with nanoparticles can be utilized to create activatable nanosensors based on radioactive decay. Blue Cerenkov light is generated by the passage of particulate radioactive emissions (such as positrons or electrons) through tissues. Cerenkov light allows for optical imaging of radiotracers with highly sensitive cameras. Based on the results of our previously demonstrated in vivo Cerenkov luminescence imaging from radiotracers, the overall objective of this application is to sense enzymatic activities associated with cancer in vivo using radiometals and modified nanoparticles In this new R01 application, cancer-related endoproteases modulate the physical interaction between different nanoparticles and a radiometals as Cerenkov emitters. Our hypothesis will be tested in three specific aims on the basis of strong preliminary data from our lab: in Specific Aim (1), we will explore different design principles of the nanoparticles in evaluating the efect of diferent coatings and radiometals onto the Cerenkov emission; in Specific Aim (2), we will sense the enzymatic activity of specific endoproteases (matrix metalloproteinase-2, cathepsin B and urokinase-type plasminogen activator) in vivo using Cerenkov imaging; in Specific Aim (3), the objective is to implement a process to quantify the nanosensor's activation and thus the enzymatic activity. This is based on a combination of Cerenkov imaging with positron emission tomography (PET) imaging. PET imaging allows for an independent quantification of the nanosensors in the tumor (using the Specific Uptake Value (SUV)) irrespective of their current activation state. We propose an inherent method to correct for the tissue attenuation and to perform a relative quantification of the signal and thus enzymatic activity. We believe that the proposed research constitutes an innovative direction and a paradigm shift in molecular imaging as it allows for sensing of enzymatic activity with radiotracers with an optical read-out, combining the unique sensitivity of PET and optical imaging together. The contribution of the proposed research is significant as it expands the potential application for nuclear imaging. It provides an entire new path for radiotracers to detect relevant biological signals. These nanosensors could ultimately find their way into the clinical realm, for example in intraoperative imaging.