A specific and adaptable approach to track CD206+ macrophages by molecular MRI and fluorescence imaging
Year: 2024
Type: article
Abstract: Rationale: The mannose receptor (CD206, expressed by the gene Mrc1) is a surface marker overexpressed by anti-inflammatory and pro-tumoral macrophages.As such, CD206 + macrophages play key roles in the immune response to different pathophysiological conditions and represent a promising diagnostic and therapeutic target.However, methods to specifically target these cells remain challenging.In this study, we describe a multi-mannose approach to develop CD206-targeting fluorescent and MRI agents that specifically and sensitively detect and monitor CD206 + macrophage immune response in different disease conditions.Methods: We designed and synthesized fluorescent agents MR1-cy5 and MR2-cy5, and MRI agents Mann2-DTPA-Gd and MannGdFish.Cellular assays using pro-inflammatory and anti-inflammatory macrophages differentiated from RAW 264.7 cells were performed, and signals were detected by fluorescence microscopy and inductively coupled plasma mass spectrometry (ICP-MS) to validate specificity in vitro.In vivo specificity and efficacy of the agents were evaluated by MRI in a subcutaneous wound healing model and experimental glioma with Mrc1 +/+ without and with D-mannose treatment, Mrc1 +/-, and Mrc1 -/-mice, and in stroke.One-way ANOVA and two-way ANOVA tests were used for data analysis.P < 0.05 was considered statistically different.Results: Both in vitro fluorescence imaging with MR2-cy5, ICP-MS with Mann2-DTPA-Gd, and in vivo MRI in Mrc1 -/-mice confirmed the specificity of our approach.Mann2-DTPA-Gd MRI can track the changes of CD206 + macrophages at different stages of wound healing, correlating well with flow cytometry data using another anti-inflammatory macrophage marker (arginase-1).The specificity and efficacy of Mann2-DPTA-Gd were further validated in experimental glioma, in which Mann2-DTPA-Gd imaging detected CD206 + tumor-associated macrophages (TAMs), demonstrated significantly decreased signals in Mrc1 +/-mice and Mrc1 -/-mice, and tracked treatment changes in D-mannose-treated Mrc1 +/+ mice.Furthermore, Mann2-DTPA-Gd can report microglia/macrophages and correlate with histology in stroke.The more Gd-stable agent MannGdFish demonstrated similar efficacy as Mann2-DTPA-Gd in vivo with favorable biodistribution and pharmacokinetics.Conclusion: We have developed a fluorescent agent (MR2-cy5) and MRI agents (Mann2-DTPA-Gd and MannGdFish) with two mannose moieties that are highly specific to CD206 and can track CD206 + macrophages in disease models of wound healing, tumor, and neurological disease.Importantly, MannGdFish, with its high specificity, stability, favorable biodistribution, and pharmacokinetics, is a promising translational candidate to noninvasively monitor CD206 + macrophages in repair/regeneration and tumors in patients.In addition, with the specific binding motif to CD206, other imaging modalities and therapeutic agents could also be introduced for theranostic applications.
Source: Theranostics
DOI: 10.7150/thno.96488
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,671
OpenAlex ID: W4405256153