Imaging Rheumatoid Arthritis in Mice Using Combined Near Infrared and 19F Magnetic Resonance Modalities

Hieu Vu-Quang,Niels Chr. Nielsen,Frederik Dagnaes-Hansen,Jørgen Kjems,Ping Song,Mads Sloth Vinding,Maria Jakobsen

doi:10.1038/s41598-019-50043-0

Hieu Vu-Quang, Niels Chr. Nielsen + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-50043-0

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease that causes pain and tissue destruction in people worldwide. An accurate diagnosis is paramount in order to develop an effective treatment plan. This study demonstrates that combining near infrared (NIR) imaging and 19F MRI with the injection of labelled nanoparticles provides high diagnostic specificity for RA. The nanoparticles were made from poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (NP) or PLGA-PEG-Folate (Folate-NP), loaded with perfluorooctyl bromide (PFOB) and indocyanine green (ICG) and evaluated in vitro and in a collagen-induced arthritic (CIA) mouse model. The different particles had a similar size and a spherical shape according to dynamic light scattering (DLS) and transmission electron microscopy (TEM). Based on flow cytometry and 19F MRI analysis, Folate-NP yielded a higher uptake than NP in activated macrophages in vitro. The potential RA-targeting ability of the particles was studied in CIA mice using NIR and 19F MRI analysis. Both NP and Folate-NP accumulated in the RA tissues, where they were visible in NIR and 19F MRI for up to 24 hours. The presence of folate as a targeting ligand significantly improved the NIR signal from inflamed tissue at the early time point (2 hours), but not at later time points. Overall, these results suggest that our nanoparticles can be applied for combined NIR and 19F MRI imaging for improved RA diagnosis.

Highlights

Macrophages play a central role in Rheumatoid arthritis (RA)
We describe and characterize two novel PFOBand indocyanine green (ICG)-loaded nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG) (NP) or folate-conjugated PLGA-PEG (Folate–NP) and demonstrate their ability to accumulate in activated macrophages in order to diagnose RA in a mouse model by bimodal NIR/19F MRI imaging
The fluorophore Cou[6] was used to track nanoparticle uptake in vitro (NP/Cou[6] and NP-Folate/ Cou6), while NP/ICG and NP-Folate/ICG were used for NIR imaging and MRI in vivo

Summary

Introduction

Macrophages play a central role in RA. An abundance of macrophages is found in the inflamed synovial membrane/fluid and the pannus of inflammatory vascular tissue in RA-affected joints, when compared with healthy controls. It is essential to develop new particles with prolonged half-life and specific targeting to activated macrophages in order to achieve the accumulation in arthritic joints required for diagnostic accuracy and treatment efficacy. PLGA-PEG has been conjugated with folic acid to target the overexpressed folate receptors on the surface of certain cancer cells in tumor and activated macrophages in RA joints[3,4,12,13]. NIR imaging has disadvantages that make it less applicable for clinical use, such as a lack of anatomical detail in the images, high and unspecific fluorescent background, and low tissue penetration. Many fluorinated agents are nontoxic, inert and conveniently monitored using 19F MRI This imaging technique is essentially background-free due to the lack of endogenous 19F sources in living systems. By combining 19F MRI and conventional 1H MRI it is possible to create highly specific images consisting of 1H-based anatomical features and the 19F-based detection of the fluorinated compounds

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