Zirconium-89 oxine complex as a cell labeling agent for positron emission tomography
Inventors
Sato, Noriko • Wu, Haitao • Griffiths, Gary L. • Choyke, Peter L.
Assignees
US Department of Health and Human Services
Publication Number
US-10556916-B2
Publication Date
2020-02-11
Expiration Date
2035-04-01
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Abstract
The invention provides a method of preparing a 89Zr-oxine complex of the formula. The invention also provides a method of labeling a cell with the 89Zr-oxine complex and a method for detecting a biological cell in a subject comprising administering the 89Zr-oxine complex to the subject.
Core Innovation
The invention provides a method of preparing a 89Zr-oxine complex and using this complex as a cell labeling agent for positron emission tomography (PET). The method includes combining oxine and 89ZrCl4 in hydrochloric acid at room temperature, neutralizing the mixture with an alkaline solution, thereby generating the 89Zr-oxine complex, and optionally isolating it via organic solvent extraction. The labeled complex is used to label various biological cells or microorganisms by contacting them in a buffer solution, enabling detection through PET imaging upon administration to a subject.
The problem being addressed is the difficulty in effectively tracking cell-based therapies in vivo over multiple days without interfering with cell viability or function. Existing imaging techniques, such as bioluminescence, magnetic resonance imaging (MRI), and single photon emission tomography (SPECT), have limitations including poor tissue penetration, limited sensitivity, low resolution, or short half-lives of labeling agents. The invention aims to provide a labeling method with a long-lived positron emitting radioisotope that allows sensitive, whole body cell tracking without significant impacts on cell survival, proliferation, or function.
The 89Zr-oxine complex offers a long half-life PET emitter (half-life of 3.27 days) that is capable of labeling various cell types efficiently at room temperature or below, without requiring active cellular transport. Experimental results demonstrate that labeled cells, including hematopoietic cells, retain viability, proliferation, phenotype, and function after labeling and can be tracked using PET imaging. The invention also outlines applications such as monitoring cell migration, distribution, and therapeutic efficacy in subjects, as well as a kit comprising the complex and instructions for labeling biological cells or microorganisms for clinical or research use.
Claims Coverage
The patent includes claims covering methods of labeling cells or microorganisms with the 89Zr-oxine complex and additional features related to labeling and washing steps.
Method of labeling cells or microorganisms with 89Zr-oxine complex
Contacting biological cells or microorganisms with a 89Zr-oxine complex of specific formula to achieve labeling for detection purposes.
Washing of labeled cells or microorganisms
Removing non-internalized 89Zr from 89Zr-oxine complex-labeled cells or microorganisms to ensure specific labeling.
Labeling of healthy cells
Application of the labeling method specifically to healthy cells.
Labeling of specific healthy cell types
Labeling cells including T cells, natural killer cells, dendritic cells, macrophages, monocytes, B cells, myeloid cells, platelets, stem cells, progenitors, mesenchymal cells, epithelial cells, neural cells, skeletal myoblasts, or pancreatic islet cells with the 89Zr-oxine complex.
Simultaneous labeling with additional agents
Use of a buffer solution comprising a second labeling agent allowing simultaneous labeling of the cell or microorganism with both 89Zr-oxine complex and another labeling agent.
The claims cover methods of labeling cells or microorganisms with the 89Zr-oxine complex, including washing steps to remove free isotope, application to various healthy cell types, and co-labeling with additional agents for enhanced imaging capabilities.
Stated Advantages
Enables long-term tracking of labeled cells for several days due to the long half-life of 89Zr.
Provides high sensitivity and resolution PET imaging with significantly lower radiation doses compared to SPECT.
Allows labeling at room temperature or below, without requiring active cellular transport.
Does not significantly interfere with cell viability, proliferation, phenotype, or function after labeling.
Enables whole body monitoring of cell migration and distribution using PET imaging.
Can be used with a variety of cell types including immune cells and stem cells.
Offers improved imaging capabilities for monitoring cell-based therapies compared to currently available methods.
Documented Applications
Tracking migration and cellular distribution of therapeutic cells such as T cells, natural killer cells, dendritic cells, and bone marrow cells in subjects.
Monitoring the efficacy and trafficking of cell-based therapies for cancer, autoimmune diseases, inflammatory diseases, ischemic diseases, genetically deficient disease states, and malignancies.
Labeling of microorganisms including infectious pathogens or human microbiome for detection in subjects.
Use in bone marrow transplantation to assess cell engraftment and homing.
Use in adoptive transfer of immune cells targeting tumors to visualize tumor infiltration and therapeutic effect.
Combined imaging modalities involving PET-MRI and optical imaging by co-labeling cells with MR imaging agents and fluorescent dyes.
Use in research or clinical settings for non-invasive and repeated imaging of cells or microorganisms in vivo.
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