Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Lu, Yaobin; Parker, Nikki; Kleindl, Paul J.; Cross, Vicky; Wollak, Kristin N.; Westrick, Elaine; Stinnette, Torian W.; Gehrke, Mark A; Wang, Kevin; Santhapuram, Hari Krishna R.; You, Fei; Hahn, Spencer; Vaughn, Jeremy F.; Klein, Patrick; Vlahov, Iontcho R.; Low, Philip S.; Leamon, Christopher P.

doi:10.2119/molmed.2015.00040

Cited by 20 publications

(12 citation statements)

References 43 publications

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“…Therefore, FR-β expression distinguishes individuals with NASH in this study. A host of published research on FR-β expression in immune cells (Lu et al 2015, Reddy et al 1999, Shen et al 2015, Shillingford et al 2012 as well as reports of high expression levels of FR-β in arthritis, lupus and several cancers (Low & Kularatne 2009, Varghese et al 2007 supports the findings we have noted in this study. The activation of macrophages and subsequent FR-β expression in NASH may well be a promising indicator for both diagnostic and therapeutic purposes as it has for other inflammatory disease (Baffy 2009, Gadd et al 2014.…”

Section: Discussionsupporting

confidence: 90%

“…As a result, the development of an effective diagnostic for NASH has been elusive. FR-β is an proven marker of activated macrophages in inflammatory disease states such rheumatoid arthritis, systemic lupus erythematosus, and many cancers (Kraus et al 2016, Lu & Low 2012, Lu et al 2015, Lu et al 2011, Varghese et al 2007. FR-β is also an important mediator of macrophage homing and migration mechanisms (Machacek et al 2016), and is a wellcharacterized target for pharmaceutical intervention for inflammatory diseases and cancers (Low & Kularatne 2009, Sega & Low 2008, Varghese et al 2007.…”

Section: Discussionmentioning

confidence: 99%

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Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Lake

Hardwick

Leamon

et al. 2019

Toxicology and Applied Pharmacology

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INTRODUCTION: Nonalcoholic steatohepatitis (NASH) afflicts 20-36% of individuals with nonalcoholic fatty liver disease (NAFLD). A lipotoxic hepatic environment, altered innate immune signaling and inflammation are defining features of progression to NASH. Activated resident liver macrophages express folate receptor beta (FR-β) which may be an indicator of progression from steatosis to NASH. The goals of this study were to characterize FR-β protein expression in human NAFLD and rodent models of NASH, and demonstrate liver targeting of an FR-β imaging agent to the liver of a rodent NASH model using FR-β. METHODS: Rat liver lysates from methionine choline deficient (MCD) fed rats, high fat diet (HFD) and methionine choline sufficient (MC+) rat controls were analyzed for hepatic FR-β protein. The FR-β-targeted agent, Etarfolatide was injected into MCD and MC+-fed C57BL/6 mice for efficient FastSPECT hepatic imaging. Additionally, FR-β expression across the stages of human NAFLD from normal to NASH was assessed. RESULTS: FastSPECT images show targeting of Etarfolatide to the liver of mice fed 8 weeks of MCD diet but not control-fed mice. The MCD rat model exhibited significantly increased protein expression of hepatic FR-β in contrast to HFD or normal samples. Similarly human liver samples categorized as NASH Fatty or NASH Not Fatty showed elevated FR-β protein when compared to normal liver. FR-β transcript expression levels were elevated across both NASH Fatty and NASH Not Fatty samples.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Lake

Hardwick

Leamon

et al. 2019

Toxicology and Applied Pharmacology

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“…In addition to MTX, antiarthritic effects elicited through FR β targeting have been reported for folate-conjugated immunotoxins [ 29 ] and various folate-conjugated drugs [ 30 , 41 , 42 ]. Since FR β is primarily expressed on activated macrophages [ 27 , 28 ], microenvironmental conditions in liver and spleen will be of importance for FR β expression and macrophage polarization.…”

Section: Resultsmentioning

confidence: 99%

Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [¹⁸F]Fluoro-PEG-Folate

Chandrupatla

Jansen

Mantel

et al. 2018

Contrast Media & Molecular Imaging

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Background In rheumatoid arthritis, articular inflammation is a hallmark of disease, while the involvement of extra-articular tissues is less well defined. Here, we examined the feasibility of PET imaging with the macrophage tracer [18F]fluoro-PEG-folate, targeting folate receptor β (FRβ), to monitor systemic inflammatory disease in liver and spleen of arthritic rats before and after methotrexate (MTX) treatment. Methods [18F]Fluoro-PEG-folate PET scans (60 min) were acquired in saline- and MTX-treated (1 mg/kg, 4x) arthritic rats, followed by tissue resection and radiotracer distribution analysis. Liver and spleen tissues were stained for ED1/ED2-macrophage markers and FRβ expression. Results [18F]Fluoro-PEG-folate PET and ex vivo tissue distribution studies revealed a significant (p < 0.01) 2-fold lower tracer uptake in both liver and spleen of MTX-treated arthritic rats. Consistently, ED1- and ED2-positive macrophages were significantly (p < 0.01) decreased in liver (4-fold) and spleen (3-fold) of MTX-treated compared with saline-treated rats. Additionally, FRβ-positive macrophages were also significantly reduced in liver (5-fold, p < 0.005) and spleen (3-fold, p < 0.01) of MTX- versus saline-treated rats. Conclusions MTX treatment reduced activated macrophages in liver and spleen, as markers for systemic inflammation in these organs. Macrophage PET imaging with [18F]fluoro-PEG-folate holds promise for detection of systemic inflammation in RA as well as therapy (MTX) response monitoring.

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“…CD14 + monocytes showed an increased expression of CD11b, and when ex vivo stimulated, increased production of IL-1β and IL-6 is observed ( 37 ). Interestingly, PI3K/mTOR and MAPK signaling pathways are also activated in RA monocytes ( 36 , 38 ), and inhibiting mTOR reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss ( 39 , 40 ). In addition, epigenetic changes have been suggested to play a role, although no genome wide epigenetic analyses in monocytes/macrophages have been performed.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

2018

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During induction of trained immunity, monocytes and macrophages undergo a functional and transcriptional reprogramming toward increased activation. Important rewiring of cellular metabolism of the myeloid cells takes place during induction of trained immunity, including a shift toward glycolysis induced through the mTOR pathway, as well as glutaminolysis and cholesterol synthesis. Subsequently, this leads to modulation of the function of epigenetic enzymes, resulting in important changes in chromatin architecture that enables increased gene transcription. However, in addition to the beneficial effects of trained immunity as a host defense mechanism, we hypothesize that trained immunity also plays a deleterious role in the induction and/or maintenance of autoimmune and autoinflammatory diseases if inappropriately activated.

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Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Cited by 20 publications

References 43 publications

Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [¹⁸F]Fluoro-PEG-Folate

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

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Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Cited by 20 publications

References 43 publications

Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [18F]Fluoro-PEG-Folate

The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders

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Product

Resources

About

Imaging and Methotrexate Response Monitoring of Systemic Inflammation in Arthritic Rats Employing the Macrophage PET Tracer [¹⁸F]Fluoro-PEG-Folate