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（CL）成像（CLI）是一种新的成像方法