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：切伦科夫发光 (CL) 成像 (CLI) 是一种新的成像方法，它利用 放射性示踪剂衰变过程中发出的光。与荧光成像相比，目前只有很少的 由于药物已在临床上可用，CLI 可以利用丰富的临床使用的特定放射性示踪剂来进行光学治疗 成像，例如手术期间。我们已经演示了临床前 CLI 应用程序和临床 CLI。 然而，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 介导的光激活需要不切实际的高剂量。建议的解决方案： 为了克服这些挑战，我们假设我们可以 (i) 探索短波红外 (SWIR) 部分 环境光下 CLI 的切伦科夫光谱（目标 1）； (ii) 使用临床放射性示踪剂和 癌细胞的标志是激活肿瘤中的前药以实现新的治疗范例（目标 2）。我们提出这些 两个独立的具体目标：在目标 1 中，我们将探索 900-1300 nm 光谱范围内的 SWIR CLI。这 光谱范围具有显着减少自发荧光、吸收和散射的优点，并提供 更高的深度穿透力，产生具有更高对比度和分辨率的图像。临床上尚无 经批准在该领域开展业务的代理商。理论预测表明，广谱 CL 应具有 还有 SWIR 组件 (iCL)。我们现在证明 iCL 确实可以从临床放射性示踪剂中检测到 使用专门的相机。考虑到人眼检测到的光来自大约。 400到700纳米是可行的 使用非 SWIR 发射 LED 照明，使 iCL 成像 (iCLI) 能够在光线充足的房间内进行，而无需 任何外壳。这将 CLI 从成像过程中需要特殊的强制完全黑暗中解放出来。 外壳并限制了进一步的临床应用。目标 2 关注放射性示踪剂激活的前药 多恶唑烷硼酸盐仅通过活性氧 (ROS) 在肿瘤中激活。 ROS 生成通过 放射性示踪剂的放射分解将增加已经增加的 ROS 水平，这是肿瘤中癌症的标志， 结合提供高度癌症特异性的激活机制，可以保护正常细胞 调节 ROS 水平，仅查看示踪剂的背景水平。高效力（IC50 约为 5 nM）使得 这是一种由放射性示踪剂激活的理想试剂，放射性示踪剂的含量非常低。通过添加erastin 为了进一步增加ROS，我们可以通过药理加强治疗。另外，这种方法可以 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 炎症药物进一步降低了这些患者的生活质量。总而言之，我们的工作不仅令人感动 CL 进一步进入新领域，但也增加了全新的成像和治疗范例。这个延续 我们的工作意义重大，因为我们不仅能够扩大 CL 的范围，还能引入新的疗法 用同位素接近。 SWIR CL 以及放射性示踪剂激活药物的前所未有的概念是 高度创新。