Cerenkov 2.0 – Cerenkov-activated agents for imaging and therapy

Cerenkov 2.0 — 用于成像和治疗的 Cerenkov 激活剂

• 批准号: 10644155
• 负责人: Jan Grimm
• 金额: $ 71.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10644155
• 关键词: Alkylating Agents; Anti-Inflammatory Agents; Antibody-drug conjugates; Antigens; Area; Arthritis; Borates; Cells; Charge; Clinic; Clinical; Clinical Trials; DNA; Darkness; Data; Disadvantaged; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Elementary Particles; Exclusion; Eye; FOLH1 gene; Fluorescent Dyes; Human; Image; Image-Guided Surgery; In Vitro; Inflammatory; Isotopes; J591 Monoclonal Antibody; Light; Linear Accelerator Radiotherapy Systems; Lymphography; Malignant Neoplasms; Mediating; Normal Cell; Operative Surgical Procedures; Patient imaging; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Positron; Price; Prodrugs; Publications; Quality of life; Radio; Radioactive; Radioactivity; Reactive Oxygen Species; Research; Resected; Resolution; Sentinel Lymph Node; Short Waves; Shortwave Infrared Imaging; Signal Transduction; Specificity; Systemic disease; Tissues; Toxic effect; Tracer; Travel; Vasculitis; Work; absorption; cancer cell; cherenkov imaging; clinical application; clinical imaging; clinically relevant; dosimetry; erastin; fluorescence imaging; fluorodeoxyglucose; imaging agent; imaging modality; imaging system; in vivo; innovation; light intensity; lightspeed; luminescence; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optical imaging; photoactivation; pre-clinical; public health relevance; radiotracer; side effect; spatiotemporal; success; tool; tumor; uptake

SUMMARY. The problem: Cerenkov luminescence (CL) imaging (CLI) is a new imaging method that utilizes light emitted during the decay of radiotracers. In contrast to fluorescence imaging, where currently only very few agents are clinically available, CLI can tap into the wealth of clinically used specific radiotracers for optical imaging, e.g. during surgery. We already have demonstrated pre-clinical CLI applications as well as clinical CLI. Yet, due to its very low signal intensity the versatility of CL remains limited. Imaging requires strict exclusion of ambient light, and CL-mediated photoactivation demands unrealistic high doses. Proposed solution: To overcome these challenges, we hypothesized that we could (i) explore the short-wave infrared (SWIR) part of the Cerenkov spectrum for CLI under ambient light (Aim 1); and (ii) utilize clinical radiotracers together with a hallmark of cancer cells to activate a prodrug in tumors for a new therapy paradigm (Aim 2). We propose these two independent specific aims: In Aim 1, we will explore SWIR CLI in the spectral range of 900-1300 nm. This spectral range has the advantage of significantly reduced autofluorescence, absorption and scatter and provides much higher depth penetration, yielding images with much higher contrast and resolution. There are no clinical approved agents operating in this area. Theoretical prediction shows that the broad-spectrum CL should have also a SWIR component (iCL). We now demonstrated that iCL can indeed be detected from clinical radiotracers using specialized cameras. Considering that human eyes detect light from ca. 400 to 700 nm it will be feasible to use non-SWIR emitting LED lightening, enabling iCL imaging (iCLI) to be carried out in a well-lit room without any enclosure. This liberates CLI from the mandatory total darkness during imaging that required special enclosures and limited further clinical applications. Aim 2 focuses around or radiotracer-activated prodrug doxazolidine-borate that is only activated in tumors via reactive oxygen species (ROS). The ROS generated via radiolysis from radiotracers will add to the already increased ROS levels present as cancer hallmark in tumors, providing in combination a highly cancer-specific activation mechanism that spares normal cells that have regulated ROS levels and only see background levels of the tracer. The high potency (IC50 of ~5 nM) makes this an ideal agent to be activated by radiotracers, which are present only in very low amounts. By adding erastin to further increases ROS, we can pharmacologically enhance the therapy. In addition, this approach could be used for other drugs, e.g. to treat severe inflammatory diseases such as arthritis or vasculitis where anti- inflammatory drugs further reduce the quality of life in these patients. Taken together, our work is not only moving CL further into new realms but is also adding an entirely new imaging and therapy paradigm. This continuation of our work is significant, as we are able to expand the scope of not only CL but also to introduce new therapy approaches with isotopes. The unprecedented concepts of SWIR CL as well as radiotracer-activated drugs are highly innovative.

概括。问题：Cerenkov发光（CL）成像（CLI）是一种利用的新成像方法 放射性示例腐烂期间发出的光。与荧光成像相反，目前只有极少数 代理在临床上可用，CLI可以利用用于光学的临床使用特定的放射性示踪剂 成像，例如手术期间。我们已经证明了临床前CLI应用以及临床CLI。 但是，由于其信号强度非常低，CL的多功能性仍然有限。成像需要严格排除 环境光和CL介导的光活化需要不切实际的高剂量。建议的解决方案： 克服这些挑战，我们假设我们可以（i）探索短波红外（SWIR）的一部分 在环境光下的CERENKOV光谱（AIM 1）； （ii）将临床放射性示例与A一起使用 癌细胞的标志是激活肿瘤中的前药以进行新的治疗范式（AIM 2）。我们提出了这些 两个独立的特定目标：在AIM 1中，我们将探索900-1300 nm光谱范围内的SWIR CLI。这 光谱范围具有显着降低自动荧光，吸收和散射的优点，并提供 深度渗透率更高，产生具有更高对比度和分辨率的图像。没有临床 在该领域运营的批准代理。理论预测表明，广谱CL应该具有 还有SWIR组件（ICL）。我们现在证明确实可以从临床放射性示例中检测到ICL 使用专用摄像机。考虑到人的眼睛检测到Ca的光。 400至700 nm是可行的 要使用非SWIR发射LED闪电，使ICL成像（ICLI）可以在没有光线的房间内进行 任何外壳。这使CLI从成像期间的强制性完全黑暗中解放出来，需要特别 外壳和进一步的临床应用。 AIM 2聚焦或放射性示波器激活前药 多沙唑胺 - 纤维化物仅通过活性氧（ROS）在肿瘤中激活。通过生成的ROS 放射性示踪剂的放射分解将增加已升高的ROS水平，作为肿瘤中的癌症标志， 提供一种高度癌症特异性的激活机制，该机制可保留具有 调节的ROS水平，仅参见示踪剂的背景水平。高效力（〜5 nm的IC50）使得 这是一个理想的药物，可以被放射性示例激活，仅存在非常低的量。通过添加Erastin 为了进一步增加ROS，我们可以从药理上增强治疗。另外，这种方法可能是 用于其他药物，例如治疗严重的炎症性疾病，例如关节炎或血管炎 炎性药物进一步降低了这些患者的生活质量。综上所述，我们的工作不仅在移动 CL进一步进入新领域，但也增加了一个全新的成像和治疗范式。这个延续 我们的工作意义重大，因为我们不仅可以扩大CL的范围，还可以引入新的疗法 同位素接近。 SWIR CL以及放射性示例激活的药物的前所未有的概念是 高度创新。