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经被设计用来检测和可视化体内的分子活动。然而，尽管核成像高度敏感，但由于以下原因，核成像在感知生物活动方面受到了相当大的限制 身体上无法将放射性“开”或“关”为了填补这一空白，我们假设 切伦科夫发光成像与纳米颗粒相结合，可用于制造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微粒放射性发射(如正电子或电子)通过组织产生的。切伦科夫光可以用高灵敏度的相机对放射性示踪剂进行光学成像。根据我们先前证明的放射性示踪剂体内切伦科夫发光成像的结果，这项应用的总体目标是检测相关的酶活性 在这一新的R01应用中，使用放射性金属和修饰纳米颗粒的体内癌症，癌症相关内切酶调节不同纳米颗粒和放射性金属之间的物理相互作用，作为切伦科夫发射器。我们的假设将基于我们实验室强大的初步数据在三个特定目标的基础上进行验证：特定目标(1)，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；在特定目标(2)，我们将使用切伦科夫成像技术在体内检测特定内切酶(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物)的酶活性；在特定目标(3)，我们的目标是实现一个过程来量化纳米传感器的激活，从而酶活性。这是基于切伦科夫成像和正电子发射断层扫描(PET)成像的组合。PET成像允许对肿瘤中的纳米传感器进行独立的量化(使用特定摄取值(SUV))，而与它们当前的激活状态无关。我们提出了一种固有的方法来校正组织的衰减，并对信号进行相对量化，从而实现酶的活性。我们认为，拟议的研究代表了分子成像的一个创新方向和范式转变，因为它允许通过光学读出的放射性示踪剂感测酶活性，将PET和光学成像的独特敏感性结合在一起。这项拟议的研究具有重要的贡献，因为它扩大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.