Inflammation is an important factor in many (chronic) diseases, such as rheumatoid arthritis, inflammatory bowel disease, cardiovascular disease, and diabetes. The knowledge about the underlying mechanisms of inflammation in these diseases is limited. Nuclear molecular imaging offers a solution to visualize these processes.
Molecular imaging can help to understand these underlying mechanisms and be used to guide and monitor therapeutic intervention. Moreover, new biomarkers for inflammatory diseases can be identified. These same biomarkers could be used as a target for novel therapies.
Three nuclear imaging strategies were successfully used for clinical imaging of inflammatory disease:
- Unspecific targeting of inflammation
- Targeting of a specific marker involved in inflammation
- Labeling of immune cells
Unspecific inflammation imaging.
Imaging of inflammation can be performed by using tracers that target common features of inflammation. Some of these features are increased tissue permeability and increased metabolism of (immune) cells.
For example, high accumulation of the glucose analog F-18-fluorodeoxyglucose (F-18-FDG) is observed in inflamed tissue due to the increased energy demand of inflammatory cells. The location and severity of inflammation of many origins can be visualized by F-18-FDG PET/CT.
Inflammation can also be detected by radiolabeled proteins, such as IgG or albumin. The accumulation in the site of inflammation is due to increased blood flow and Enhanced (vascular) Permeability and Retention (EPR).
The same mechanism is used for the targeting of inflammation by liposomes and nanoparticles. By loading these particles with drugs, high concentrations of the drug can be delivered at the site of inflammation. By radiolabeling the liposomes and nanoparticles and consecutive imaging, the targeting of the particles can be examined prior to therapy. This way, patients can be stratified, and the efficacy of the therapy can be predicted. However, the above-mentioned imaging strategies are not specific to inflammation. Therefore, they can not unravel the specific cellular and molecular mechanisms in inflammatory disease.
Targeting of inflammation in specific markers.
Efforts have been made to develop specific targeting agents for inflammation imaging. Cytokines play a key role in the onset and sustained inflammation. By radiolabeling of cytokines specific pathways of inflammatory disease can be visualised.
For example, Interleukin-2 (IL-2) binds with high affinity to the IL-2 receptors overexpressed on activated T-lymphocytes. IL-2 was labeled with a variety of radionuclides and evaluated in preclinical and clinical studies in various diseases. For instance, inflammatory bowel disease (Crohn’s disease) and in oncology.
Pentixafor, targeting an inflammation specific biomarker chemokine receptor type 4 (CXCR-4) was developed. CXCR-4 has a particular rich receptor expression on macrophages and T- cells. By labeling Pentixafor with gallium-68, PET can visualize inflammation. This method generates specific information on macrophage and T-cell involvement in inflammatory disease.
Several therapeutic monoclonal antibodies have been developed and used for the treatment of inflammatory diseases, such as IBD, rheumatoid arthritis and psoriasis.
Monoclonal antibodies targeting various molecular targets (e.g., interferon gamma and α4β7) have been used to treat these diseases. However, although patients benefit from therapy with these antibodies, a large portion still do not respond to this treatment. Nuclear imaging could be helpful in distinguishing responders from non- responders prior to instalment of the treatment. This will create a personalised treatment blueprint for the individual patient, preventing over- or undertreatment.
Cell labeling for nuclear imaging of inflammation.
Cell labeling is an innovative approach for imaging inflammatory disease. Leukocytes, isolated from the peripheral blood of the patient, are radiolabeled and reinfused to the patient for detection of inflammation. However, this method is rather unspecific. Recently, immune cells are isolated and stimulated ex vivo to target specific disease processes for therapeutic purpose.
For example, chimeric antigen receptor T-cells (CAR-T cells) are used to prime T-cells to target specific diseases (e.g. tumors). These CAR-T cells can be labeled in various ways to track the cells in the human body to prove homing of the cells to the site of interest and predict therapeutic response then:
- Cells can be labeled by MRI-nanoparticles containing the contrast agent gadolinium, iron oxide or fluorine-19.
- The cells can be radiolabeled with Tc-99m-HMPAO, indium-111 or zirconium-89 oxine for the detection by SPECT or PET, respectively.
Overall nuclear imaging can visualize cellular and molecular processes in inflammatory disease. This technology can be used to obtain early first-in-human data on the potential of new molecular entities.
Are you planning on using nuclear imaging in your anti-inflammatory drug development strategy? Or evaluating the possibilities?
Contact us for more information specific to the compound(s) in your pipeline.