Carbon Nanotubes—Potent Carriers for Targeted Drug Delivery in Rheumatoid Arthritis

Two types of single-walled carbon nanotubes (SWCNTs), HiPco- and carboxyl-SWCNT, are evaluated as drug carriers for the traditional anti-inflammatory drug methotrexate (MTX) and a small interfering RNA (siRNA) targeting NOTCH1 gene. The nanotubes are solubilized by PEGylation and covalently loaded with MTX. The coupling efficiency (CE%) of MTX is 77–79% for HiPco-SWCNT and 71–83% for carboxyl-SWCNT. siRNA is noncovalently attached to the nanotubes with efficiency of 90–97% for HiPco-SWCNT and 87–98% for carboxyl-SWCNT. Through whole body imaging in the second near-infrared window (NIR-II window, 1000–1700 nm), SWCNTs were found to be selectively accumulated in inflamed joints in a serum transfer mouse model. We further investigated the interactions of the siRNA/MTX loaded nanotubes with human blood and mice bone marrow cells. In human blood, both types of unloaded SWCNTs were associated with B cells, monocytes and neutrophils. Interestingly, loading with MTX suppressed SWCNTs targeting specificity to immune cells, especially B cells; in contrast, loading siRNA alone enhanced the targeting specificity. Loading both MTX and siRNA to carboxyl-SWCNT enhanced targeting specificity to neutrophils and monocytes but not B cells. The targeting specificity of SWCNTs can potentially be adjusted by altering the ratio of MTX and siRNA loaded. The combined results show that carbon nanotubes have the potential for delivery of cargo drugs specifically to immune cells involved in rheumatoid arthritis.

Download Full-text

Regulation of rheumatoid factor production by peripheral blood and synovial fluid B cells in rheumatoid arthritis

Immunology Letters ◽

10.1016/s0165-2478(97)87700-0 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 216

Author(s):

C Reparon-Schuijt

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Synovial Fluid ◽

Rheumatoid Factor ◽

Peripheral Blood ◽

Factor Production

Download Full-text

Rheumatoid Arthritis: History, Stages, Epidemiology, Pathogenesis, Diagnosis and Treatment

INTERNATIONAL JOURNAL OF TOXICOLOGICAL AND PHARMACOLOGICAL RESEARCH ◽

10.25258/ijtpr.v9i02.9052 ◽

2017 ◽

Vol 9 (02) ◽

Author(s):

Abeer Fauzi Al-Rubaye ◽

Mohanad Jawad Kadhim ◽

Imad Hadi Hameed

Keyword(s):

Rheumatoid Arthritis ◽

Medicinal Plants ◽

Systemic Disease ◽

Modern Medicine ◽

Whole Body ◽

Internal Organs ◽

Synthetic Drugs ◽

Relieve Pain ◽

Medicinal Treatment ◽

Natural Drugs

The pharmacological mechanisms of the medicinal plants traditionally used for RA in Persian medicine are discussed in the current review. Further investigations are mandatory to focus on bioefficacy of these phytochemicals for finding novel natural drugs. Rheumatoid arthritis is chronic, progressive, disabling autoimmune disease characterized by systemic inflammation of joints, damaging cartilage and bone around the joints. It is a systemic disease which means that it can affect the whole body and internal organs such as lungs, heart and eyes. Although numbers of synthetic drugs are being used as standard treatment for rheumatoid arthritis but they have adverse effect that can compromise the therapeutic treatment. Unfortunately, there is still no effective known medicinal treatment that cures rheumatoid arthritis as the modern medicine can only treat the symptoms of this disease that means to relieve pain and inflammation of joints. It is possible to use the herbs and plants in various forms in order to relieve the pain and inflammation in the joints. There are so many medicinal plants that have shown anti rheumatoid arthritis properties. So the plants and plant product with significant advantages are used for the treatment of rheumatoid arthritis. The present review is focused on the medicinal plants having anti rheumatoid arthritis activity

Download Full-text

The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

Revista de Chimie ◽

10.37358/rc.18.9.6572 ◽

2018 ◽

Vol 69 (9) ◽

pp. 2541-2545

Author(s):

Raluca Barzoi ◽

Elena Rezus ◽

Codruta Badescu ◽

Razan Al Namat ◽

Manuela Ciocoiu

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Nuclear Factor ◽

Receptor Activator ◽

Level Function ◽

Rheumatoid Polyarthritis ◽

The Impact ◽

Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

Download Full-text

P2.11-21 Usefulness of Diffusion-Weighted Whole-Body Imaging with Background Suppression in the Postoperative Follow-up Period

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.08.1721 ◽

2019 ◽

Vol 14 (10) ◽

pp. S800

Author(s):

K. Suemori ◽

M. Kataoka ◽

D. Okutani ◽

T. Fujita ◽

I. Togami ◽

...

Keyword(s):

Whole Body ◽

Background Suppression ◽

Whole Body Imaging ◽

Body Imaging ◽

Diffusion Weighted

Download Full-text

OP0178 IMAGING NEOANGIOGENESIS IN RHEUMATOID ARTHRITIS (INIRA): WHOLE-BODY SYNOVIAL UPTAKE OF A 99MTC-LABELLED RGD PEPTIDE IS HIGHLY CORRELATED WITH POWER DOPPLER ULTRASOUND

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5482 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 110.2-111

Author(s):

L. Attipoe ◽

S. Subesinghe ◽

C. Blanco-Gil ◽

M. Opena ◽

M. Rosser ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Correlation Coefficient ◽

Doppler Ultrasound ◽

Imaging Modality ◽

Power Doppler ◽

Whole Body ◽

Total Power ◽

Acquisition Time ◽

Power Doppler Ultrasound ◽

Highly Correlated

Background:Power Doppler ultrasound (PDUS) is superior to clinical examination in detecting synovitis in patients with rheumatoid arthritis (RA). Although dynamic and cheap it is impractical to scan large numbers of joints in routine clinical settings. MRI, whilst sensitive for synovitis, is expensive and routine use is limited to targeted joints. Bone scintigraphy produces whole body images but due to limited specificity is not routinely used.99mTc-maraciclatide (Serac Healthcare) is a radiolabelled tracer which binds with high affinity to integrin αvβ3, a cell-adhesion molecule up-regulated on neoangiogenic blood vessels. It therefore has the potential to image synovial inflammation at the whole-body level. We previously showed in a pilot study that uptake was seen in the inflamed joints of five RA patients and that this correlated with PDUS. This study explores correlation with PDUS in a larger groups of patients with varied disease activity.Objectives:To determine the correlation between ultrasound and99mTc-maraciclatide imaging in patients with rheumatoid arthritis.Methods:50 patients with RA fulfilling ACR 2010 classification criteria were recruited. Patients underwent an ultrasound scan of 40 joints with grey scale (GS) and PD quantification. Each joint was scored on a scale of 0-3 for GS and PD with a total score calculated for each patient. Within 3 hours of the ultrasound patients were injected with 740 MBq of99mTc-maraciclatide. Using a gamma camera, whole body planar views and dedicated hand and foot views were taken 2 hours after injection (Figure 1). Acquisition time was 20 minutes for whole body and 20 minutes for hand and foot views.99mTc-maraciclatide images were scored as positive or negative uptake for each joint (binary score). A quantitative score was also calculated for each joint where there was uptake with this corrected for background uptake. Total binary and quantitative scores per patient were calculated.Ultrasound and99mTc-maraciclatide scores were tested for correlation with Pearson’s correlation coefficient (r). Interrater agreement for 2 scorers was calculated using kappa (ĸ) and concordance correlation coefficient (Pc).Results:Strong correlation was seen when total PDUS was compared to binary scores (r=0.92, r2=0.85) (Figure 2) and quantitative scores (r=0.85, r2=0.72). ĸ was 0.82 and 0.79 for binary and ultrasound scores respectively.Pcwas 0.82 for quantitative scores. p was <0.0005 for all results.99mTc-maraciclatide uptake was also seen in inflamed tendons/tendon sheaths. The imaging procedure was well-tolerated. There were no tracer-related adverse events.Figure 1.99mTc-maraciclatide imaging with dedicated hand and foot viewsConclusion:99mTc-maraciclatide uptake was highly correlated with PDUS highlighting its potential as an alternative imaging modality.99mTc-based planar imaging has the unique capacity to image the whole body and hence the total synovial inflammatory load in a quick acquisition. The imaging equipment to perform these scans is already widely available in radiology departments. Interpretation of scans is also much simpler compared to US/MRI. It could therefore have a role in key decision-making points in pathways for diagnosis, treatment failure, and remission prior to dose tapering.Figure 2.Correlation between total power doppler and99mTc-maraciclatide binary scoresDisclosure of Interests:None declared

Download Full-text

CO0005 C-C CHEMOKINE RECEPTOR TYPE 5 AND ITS LIGANDS CCL4, 8 AND 11 CAN LINK COVID-19, RHEUMATOID ARTHRITIS AND HYDROXYCHLOROQUINE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6801 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 213.3-214

Author(s):

M. Y. Hachim ◽

S. Hannawi

Keyword(s):

Rheumatoid Arthritis ◽

Mechanism Of Action ◽

Immune Cells ◽

Health Concern ◽

Healthy Controls ◽

Global Public Health ◽

Ccr5 Expression ◽

Disease Modifying Drugs ◽

Link Type ◽

Disease Modifying

Background:Coronavirus disease (COVID-19) caused by SARS-COV2 represents an unprecedented global public health concern with a particular burden on patients with chronic diseases and those on immune-modulating drugs. It is especially worrisome to patients with rheumatoid arthritis (RA) who are on immune suppression regimens[1]. On the other side, many reports showed and recommended the use of some Disease-Modifying Drugs commonly used to treat rheumatic diseases like hydroxychloroquine. However, the general understanding of COVID-19 characteristics in this population and the mechanism of action of these drugs in COVID-19 is still unknown[2].Objectives:Explore publicly available transcriptomic dataset of patients infected with SARS-COV2 compared to uninfected to identify differentially expressed genes (DEGs) related to the immune system that might be pathogenic in RA synovium. Then explore the effect of Disease-Modifying Drugs on their local expression that might give hints about their possible mechanism of action.Methods:RNAseq dataset (GSE147507) were retrieved using the Gene Expression Omnibus (GEO) and used to identify DEGs between infected and uninfected lung samples using BioJupies tools [3]. The DEGs were explored for common pathways using Metascape online tool (http://metascape.org) [10], as shown in figure (1). The chemokines genes were filtered out, and their common receptor (CR) was identified. The immune cells that express a higher level of the identified receptor were explored using DICE project tool (https://dice-database.org/). The expression of CR was searched in a microarray dataset (GSE77298) of synovial biopsies of RA and healthy controls. RNAseq dataset (GSE97165) of synovial biopsies taken from 19 early RA patients at baseline and after six months of Triple Disease-Modifying Anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine, and hydroxychloroquine) treatment.Results:84 DEGs were identified between uninfected and COVID-19 infected lung samples. These DEGs were enriched in pathways specific to (response to the virus, response to interferon, leukocyte activation, and chemotaxis). Interestingly, SARS-COV-2 infected lungs express more CCL4, CCL8, and CCL11; the three ligands shared the same receptor, which is CCR5. Top immune cells that express CCR5 were CD4 T memory T reg cells, Th17, Th1, and monocytes. CCR5 was significantly upregulated in RA compared to healthy controls synovium (p=0.04) and was dramatically downregulated after six months of tDMARD treatment (p=0.004), as shown in figure (2).Conclusion:Using publicly available transcriptomic datasets properly highlighted the possible beneficiary effect of DMARDs in patients with COVID-19, which can block CCR5 rich immune cells recruitment.References:[1]Favalli, E.G., et al.,COVID-19 infection and rheumatoid arthritis: Faraway, so close!Autoimmun Rev, 2020. 19(5): p. 102523.[2]Gianfrancesco, M.A., et al.,Rheumatic disease and COVID-19: initial data from the COVID-19 Global Rheumatology Alliance provider registries.The Lancet Rheumatology, 2020. 2(5): p. e250-e253.[3]Torre, D., A. Lachmann, and A. Ma’ayan,BioJupies: Automated Generation of Interactive Notebooks for RNA-Seq Data Analysis in the Cloud.Cell Systems, 2018. 7(5): p. 556-561.e3.Figure 1.Flowchart of transcriptomic analysisFigure 2.(A) Top immune cells that express CCR5 (B) CCR5 expression in synovial biopsies of RA and control (C) CCR5 expression at baseline and after 6 months of tDMARD treatment.Disclosure of Interests:None declared

Download Full-text

Doxorubicin Encapsulation in Carbon Nanotubes Having Haeckelite or Stone–Wales Defects as Drug Carriers: A Molecular Dynamics Approach

Molecules ◽

10.3390/molecules26061586 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1586

Author(s):

Leonor Contreras ◽

Ignacio Villarroel ◽

Camila Torres ◽

Roberto Rozas

Keyword(s):

Carbon Nanotubes ◽

Molecular Dynamics ◽

Drug Delivery Systems ◽

Nitrogen Doping ◽

Drug Carriers ◽

Acidic Ph ◽

Free Energies ◽

Interaction Forces ◽

Chiral Nanotubes ◽

Binding Free Energies

Doxorubicin (DOX), a recognized anticancer drug, forms stable associations with carbon nanotubes (CNTs). CNTs when properly functionalized have the ability to anchor directly in cancerous tumors where the release of the drug occurs thanks to the tumor slightly acidic pH. Herein, we study the armchair and zigzag CNTs with Stone–Wales (SW) defects to rank their ability to encapsulate DOX by determining the DOX-CNT binding free energies using the MM/PBSA and MM/GBSA methods implemented in AMBER16. We investigate also the chiral CNTs with haeckelite defects. Each haeckelite defect consists of a pair of square and octagonal rings. The armchair and zigzag CNT with SW defects and chiral nanotubes with haeckelite defects predict DOX-CNT interactions that depend on the length of the nanotube, the number of present defects and nitrogen doping. Chiral nanotubes having two haeckelite defects reveal a clear dependence on the nitrogen content with DOX-CNT interaction forces decreasing in the order 0N > 4N > 8N. These results contribute to a further understanding of drug-nanotube interactions and to the design of new drug delivery systems based on CNTs.

Download Full-text

AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1124 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1464.1-1465

Author(s):

J. Blaess ◽

J. Walther ◽

J. E. Gottenberg ◽

J. Sibilia ◽

L. Arnaud ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

B Cells ◽

Phase I ◽

Phase Ii ◽

Clinical Development ◽

Phase Iii ◽

Jak Inhibitors ◽

Exclusion Criteria ◽

Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

Download Full-text

Lipid, fatty acid, carnitine- and choline derivative profiles in rheumatoid arthritis outpatients with different degrees of periodontal inflammation

Scientific Reports ◽

10.1038/s41598-021-84122-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kathrin Beyer ◽

Stein Atle Lie ◽

Bodil Bjørndal ◽

Rolf K. Berge ◽

Asbjørn Svardal ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Inflammatory Diseases ◽

Whole Body ◽

Cross Sectional ◽

Chronic Inflammatory Diseases ◽

Periodontal Inflammation ◽

Inflammatory Status ◽

Lipid Fatty Acid

AbstractRheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.

Download Full-text