Developing a pretargeting strategy to detect Fe(II) for nuclear medicine applications

开发用于核医学应用检测 Fe(II) 的预靶向策略

• 批准号: 10441572
• 负责人: Michael John Evans
• 金额: $ 64.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441572
• 关键词: Abdomen; Acute; Animal Model; Animals; Antimalarials; Artemisinins; Benchmarking; Biodistribution; Biological; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Child; Chloroquine; Clinical; Clinical Trials; Coupling; Data; Desmoplastic; Development; Discipline of Nuclear Medicine; Disease; Dose; Dose-Limiting; Drug Kinetics; Exhibits; Generations; Genetic; Glioma; Goals; Half-Life; Hepatobiliary; Human; Image; ImmunoPET; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Injections; Iron; KRASG12D; Knowledge; Libraries; Liver; Lysosomes; Malignant Neoplasms; Measurement; Measures; Modeling; Multifocal Lesion; Mus; Neurodegenerative Disorders; Normal Cell; Normal tissue morphology; Nutrient; PET/CT scan; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathology; Pharmaceutical Preparations; Pharmacology; Physiology; Positron-Emission Tomography; Prodrugs; Radioisotopes; Reagent; Refractory; Regulation; Role; Series; Serum; Signal Transduction; Starvation; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Tracer; U251; analog; antimicrobial; base; cancer type; catalyst; clinically relevant; cohort; design; imaging modality; imaging study; improved; in vivo; inhibitor; innovation; insight; iron metabolism; liver cancer model; mouse model; optical imaging; pancreatic cancer model; protein crosslink; prototype; radioligand; radiotracer; response; sensor; small molecule; subcutaneous; success; targeted treatment; tumor; uptake; virtual

Project Abstract While it has been recognized for decades that diseased cells arising from numerous disorders exhibit altered iron metabolism compared to normal cells, only recently has it become apparent that increased concentration of cytosolic free ferrous iron (Fe2+) - the labile iron pool (LIP) – is most associated with these pathologies. Meanwhile, the overwhelming clinical success of the antimalarial artemisinin has established that LIP can be safely exploited to treat diseases in humans (including children), a milestone that has inspired us and others to develop 1,2,4-trioxolane (TRX)-based prodrugs that are activated by LIP and release drug payloads within diseased cells. Although our knowledge of the role of LIP in normal physiology and disease has increased substantially over the past 10 years, virtually all of our insights about LIP are founded on observations from cell lines. Studying LIP in vivo is a major knowledge gap that is currently impeding efforts to apply experimental LIP targeted therapies clinically. We hypothesized based on the well-studied mechanisms of TRX reactivity with LIP that a PET strategy could enable LIP measurements in vivo by sequestering a radioisotope within cells via Fe(II)-dependent protein crosslinking. We designed a prototype, 18F-TRX, and showed that its biodistribution in vivo is Fe2+-dependent, it detects diverse cancer types with an expanded LIP, and tumor uptake of 18F-TRX is directly proportional to tumor response to LIP targeting therapies. However, the tracer's rapid serum clearance (t1/2 ~28 sec) and slow hepatobiliary clearance combine to limit the overall image quality. Thus, the goal of this project is to test if a pre-targeting strategy involving macrodosing of a cold TRX reagent, followed later by a microdose of a cognate 18F-click coupling partner may improve measurements of LIP by eliminating the background signal from unreacted TRX and/or achieving better TRX exposure in tissues with LIP expansion. During Aim 1, we will synthesize and study the in vivo pharmacology of TRX- transcyclooctene (TCO) conjugates and fluoro-tetrazines to identify optimal biorthogonal click partners. During Aim 2, the optimal pre-targeting conditions will be established in tumor bearing mice using immunoPET. Imaging findings (e.g. tumor uptake, tumor to normal ratios) will be benchmarked against 18F-TRX and the 18F- tetrazine alone. During Aim 3, we will perform cohort expansion studies to acquire additional biological replicates while also studying spontaneous and orthotopic tumor models arising in abdominal tissues (e.g. liver, pancreas) that we expect to be occult on 18F-TRX imaging. If successful, defining which disease types harbor high LIP with PET provides a natural segue to clinical trials implementing the myriad experimental LIP targeted therapies currently waiting in the queue. Solving this challenge with pre-targeting would also add a new application for a venerable dosing strategy that could be broadly applied to improve the image quality of other rapidly clearing small molecule radiotracers, or perhaps even the antitumor efficacy of radioligand therapies.

项目摘要