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.

总结。问题：切伦科夫发光成像(CL)成像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。与荧光成像形成对比的是，目前只有极少数 试剂可用于临床，CLI可以利用丰富的临床使用的特定放射性示踪剂进行光学 成像，例如在手术过程中。我们已经演示了临床前CLI应用以及临床CLI。 然而，由于CL的信号强度很低，其通用性仍然有限。成像需要严格排除 环境光，而CL介导的光激活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)部分 环境光下CLI的切伦科夫谱(目标1)；和(Ii)使用临床放射性示踪剂与 为新的治疗模式激活肿瘤前药的癌细胞的标志(目标2)。我们提出这些建议 两个独立的特定目标：在目标1中，我们将探索900-1300 nm光谱范围内的SWIR化学发光。这 光谱范围的优点是显著减少了自发荧光、吸收和散射，并提供 更高的深度穿透力，产生的图像具有更高的对比度和分辨率。没有临床上的 在该地区经营的经批准的代理商。理论预测表明，广谱化学发光应该具有 也是SWIR组件(ICL)。我们现在证明，从临床放射性示踪剂中确实可以检测到icl。 使用专门的摄像头。考虑到人眼能探测到大约400到700纳米的光，这将是可行的 使用非SWIR发光LED照明，使ICL成像(ICLI)能够在光线良好的房间中执行，而无需 任何封闭物。这将CLI从映像期间的强制完全黑暗中解放出来，这需要特殊的 封闭和限制了进一步的临床应用。AIM 2聚焦于或放射性示踪剂激活的前药 多沙唑烷-硼酸盐，仅在肿瘤中通过活性氧簇(ROS)激活。通过以下方式生成的ROS 放射性示踪剂的放射分解将增加肿瘤中已经增加的作为癌症标志的ROS水平， 联合提供了一种高度癌症特异性的激活机制，使具有 调节的ROS水平，只能看到示踪剂的背景水平。高效率(IC50为~5 NM)使 这是一种理想的被放射性示踪剂激活的试剂，而放射性示踪剂的存在数量很少。通过添加擦除 为了进一步提高ROS，我们可以从药物上加强治疗。此外，这种方法可能是 用于其他药物，例如用于治疗严重的炎症性疾病，如关节炎或脉管炎 炎症性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进一步进入了新的领域，但也增加了一个全新的成像和治疗范例。这一续篇 我们的工作意义重大，因为我们不仅能够扩大CL的范围，而且还可以引入新的治疗方法 使用同位素的方法。史无前例的SWIR CL概念以及放射性示踪剂激活药物 极具创新性。