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.

摘要切伦科夫发光（CL）成像（CLI）是一种新的成像方法， 放射性示踪剂衰变时发出的光。与荧光成像相反，目前只有很少的 药物在临床上是可用的，CLI可以利用丰富的临床使用的特定放射性示踪剂， 成像，例如在手术期间。我们已经展示了临床前CLI应用程序以及临床CLI。 然而，由于其非常低的信号强度，CL的通用性仍然有限。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。建议的解决办法： 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Cerenkov光谱（目标1）;及（ii）利用临床放射性示踪剂和 癌细胞的标志，以激活肿瘤中的前药，用于新的治疗范例（Aim 2）。我们建议这些 两个独立的具体目标：在目标1中，我们将探索900-1300 nm光谱范围内的短波红外CLI。这 光谱范围具有显著降低的自发荧光、吸收和散射的优点， 更高的穿透深度，产生具有更高对比度和分辨率的图像。没有临床 在这片区域活动的特工理论预测表明，宽谱化学发光应具有 也是SWIR组件（iCL）。我们现在证明了iCL确实可以从临床放射性示踪剂中检测到 使用专门的摄像机。考虑到人眼检测来自CA的光。400到700纳米是可行的 使用非短波红外发射LED照明，使iCL成像（iCLI）能够在光线充足的房间中进行， 任何外壳。这将CLI从成像期间强制的完全黑暗中解放出来， 外壳和有限的进一步临床应用。Aim 2聚焦于放射性示踪剂激活的前体药物 多沙唑烷-硼酸盐，其仅在肿瘤中通过活性氧（ROS）活化。ROS通过以下方式产生： 来自放射性示踪剂的辐解将增加作为肿瘤中癌症标志存在的已经增加的ROS水平， 联合提供高度癌症特异性的激活机制， 调节ROS水平，并且仅看到示踪剂的背景水平。高效力（IC 50约为5 nM）使 这是一种被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。通过添加擦除 为了进一步增加ROS，我们可以进一步加强治疗。此外，这种方法可以 用于其他药物，例如治疗严重的炎性疾病，如关节炎或血管炎，其中抗- 炎性药物进一步降低了这些患者的生活质量。总的来说，我们的工作不仅令人感动， CL进一步进入新的领域，但也增加了一个全新的成像和治疗模式。这一延续 我们的工作是重要的，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。 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 极具创新性。