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      The folate receptor β as a macrophage-mediated imaging and therapeutic target in rheumatoid arthritis


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          Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor β (FRβ) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRβ harbors a nanomolar binding affinity for folic acid allowing this receptor to be exploited for RA disease imaging (e.g., folate-conjugated PET tracers) and therapeutic targeting (e.g., folate antagonists and folate-conjugated drugs). This review provides an overview of these emerging applications in RA by summarizing and discussing properties of FRβ, expression of FRβ in relation to macrophage polarization, FRβ-targeted in vivo imaging modalities, and FRβ-directed drug targeting.

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          Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay.

          The folate receptor (FR) is a valuable therapeutic target that is highly expressed on a variety of cancers. The current development of folate-targeted cancer therapies has created the need for quantitating functional FRs in clinical specimens. In this article, we report on the creation of a highly sensitive radioactive binding method for quantitatively measuring FR expression in frozen tissue homogenates. Expression was positive in approximately 89% of human ovarian carcinomas but was negligible in both mucinous ovarian carcinomas and normal ovary. Expression was also significant in carcinomas of the kidney, endometrium, lung, breast, bladder, and pancreas. Normal tissues from humans and six different laboratory species were also analyzed; surprisingly, some interspecies variability in FR expression (especially in kidney, spleen, and lung tissue) was found. Interestingly, normal human lung tissue displayed high expression levels, whereas expression in normal lung of the other species was negligible. However, considering that folate-drug conjugates fail to accumulate in the lungs of patients, the consequence of this finding was not considered to be of clinical concern. Overall, this new methodology is reliable for determining functional FR expression levels in tissues, and it could possibly be a useful clinical test to determine patient candidacy for FR-targeted therapeutics.
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            Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis.

            Previous work identified synovial sublining macrophage numbers as a potential biomarker for clinical efficacy in rheumatoid arthritis. To investigate the association between changes in infiltration of synovial macrophages and clinical improvement after antirheumatic treatment. 88 patients who participated in various clinical trials were studied. All patients underwent serial arthroscopy before initiation of treatment and after different time intervals. Immunohistochemical and digital image analysis were performed according to standardised procedures to detect changes in CD68+ synovial sublining macrophages in relationship to changes in the 28 joint count Disease Activity Score (DAS28). Statistical analysis was performed using one way analysis of variance, the independent samples t test, linear regression, and the standardised response mean (SRM). For good, moderate, and non-responders, according to the DAS28 response criteria, there was a significant difference in the change in sublining macrophages (mean (SEM) cells/mm(2) -643 (124), -270 (64), and -95 (60), respectively; p 0.8), whereas the ability to detect changes in placebo treated patients was weak (SRM <0.3). The results suggest that changes in synovial sublining macrophages can be used to predict possible efficacy of antirheumatic treatment.
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              Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers.

              The treatment and outcomes of patients with rheumatoid arthritis (RA) have been transformed over the past two decades. Low disease activity and remission are now frequently achieved, and this success is largely the result of the evolution of treatment paradigms and the introduction of new therapeutic agents. Despite the rapid pace of change, the most commonly used drug in RA remains methotrexate, which is considered the anchor drug for this condition. In this Review, we describe the known pharmacokinetic properties and putative mechanisms of action of methotrexate. Consideration of the pharmacodynamic perspective could inform the development of biomarkers of responsiveness to methotrexate, enabling therapy to be targeted to specific groups of patients. Such biomarkers could revolutionize the management of RA.

                Author and article information

                31 20 444 6685 , g.jansen@vumc.nl
                Drug Deliv Transl Res
                Drug Deliv Transl Res
                Drug Delivery and Translational Research
                Springer US (New York )
                2 October 2018
                2 October 2018
                : 9
                : 1
                : 366-378
                [1 ]Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                [2 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Radiology and Nuclear Medicine, , VU University Medical Center, ; De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funded by: FundRef http://dx.doi.org/10.13039/501100006020, Center for Translational Molecular Medicine;
                Award ID: TRACER
                Funded by: VU University Medical Center - Cancer Center Amsterdam
                Award ID: CCA—PV13/87
                Award Recipient :
                Funded by: Dutch Arthritis Association
                Award ID: NRF 09-01-404
                Funded by: ZonMw translational project
                Award ID: 95104012
                Review Article
                Custom metadata
                © Controlled Release Society 2019

                Pharmacology & Pharmaceutical medicine
                rheumatoid arthritis,macrophages,folate receptor,folate-conjugated drugs,imaging,positron emission tomography (pet)


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