A specific and adaptable approach to track CD206macrophages by molecular MRI and fluorescence imaging.

in Theranostics by Cuihua Wang, Negin Jalali Motlagh, Gregory R Wojtkiewicz, Hongzhi Yang, Hyung-Hwan Kim, John W Chen

TLDR

  • Researchers developed CD206-targeting imaging agents to detect and track specific types of immune cells in the body.
  • These agents were tested in different disease models and showed high specificity and efficacy in tracking CD206 macrophages.
  • This technology has the potential to become a valuable tool for diagnosing and treating various diseases.

Abstract

The mannose receptor (CD206, expressed by the gene) is a surface marker overexpressed by anti-inflammatory and pro-tumoral macrophages. As such, CD206macrophages 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 CD206macrophage immune response in different disease conditions.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.specificity and efficacy of the agents were evaluated by MRI in a subcutaneous wound healing model and experimental glioma withwithout and with D-mannose treatment,, andmice, and in stroke. One-way ANOVA and two-way ANOVA tests were used for data analysis. P < 0.05 was considered statistically different.Bothfluorescence imaging with MR2-cy5, ICP-MS with Mann2-DTPA-Gd, andMRI inmice confirmed the specificity of our approach. Mann2-DTPA-Gd MRI can track the changes of CD206macrophages 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 CD206tumor-associated macrophages (TAMs), demonstrated significantly decreased signals inmice andmice, and tracked treatment changes in D-mannose-treatedmice. 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-Gdwith favorable biodistribution and pharmacokinetics.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 CD206macrophages 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 CD206macrophages 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.

Overview

  • The study aims to develop CD206-targeting fluorescent and MRI agents to specifically detect and monitor CD206 macrophage immune response in different disease conditions.
  • The agents were designed and synthesized, and their specificity and efficacy were evaluated using cellular assays, fluorescence microscopy, inductively coupled plasma mass spectrometry (ICP-MS), and magnetic resonance imaging (MRI) in various disease models.
  • The primary objective is to develop a translational candidate for non-invasively monitoring CD206 macrophages in patients and exploring theranostic applications.

Comparative Analysis & Findings

  • Both fluorescence imaging with MR2-cy5 and ICP-MS with Mann2-DTPA-Gd confirmed the specificity of the CD206-targeting approach.
  • Mann2-DTPA-Gd MRI tracked changes in CD206 macrophages at different stages of wound healing, correlating well with flow cytometry data using another anti-inflammatory macrophage marker (arginase-1).
  • Mann2-DTPA-Gd imaging detected CD206 tumor-associated macrophages (TAMs) in experimental glioma, and demonstrated significantly decreased signals in mice with and without D-mannose treatment.

Implications and Future Directions

  • The development of CD206-targeting imaging agents has the potential to become a valuable diagnostic and therapeutic tool in various disease conditions.
  • Future studies should investigate the use of these agents in clinical trials to validate their safety and efficacy in patients.
  • Additional research is needed to explore the potential of these agents for theranostic applications, including targeted imaging and therapy.
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