Intracellular delivery of desulfated heparin with bile acid conjugation alleviates T cell-mediated inflammatory arthritis via inhibition of RhoA-dependent transcellular diapedesis

Kang, Jung Hoon; Hwang, Seong Youn; Sung, Su Whan; Jang, Ji Ae; Alam, Mohammad Zahangir; Hee, Keum; Kim, Sangjin; Kim, In San; Byun, Young Ho; Kang, Young Mo

doi:10.1016/j.jconrel.2014.03.029

Cited by 8 publications

(12 citation statements)

References 43 publications

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“…We have shown that 6DSHbD displayed greater binding to TNF-α stimulated HUVECs compared to unstimulated cells, followed by internalization into ECs [15]. We examined whether surface-bound modified heparin can directly block the adhesion of T cells to HUVEC monolayers under both static and dynamic conditions.…”

Section: Resultsmentioning

confidence: 99%

“…LMWH- bis DOCA (HbD), 2-O desulfated-HbD (2DSHbD), 6DSHbD and N-desulfated N-acetylated-HbD (NDSHbD) were synthesized as previously described [15, 20]. Briefly, N-deoxycholylethylamine (DOCA-NH2) or N-bisdeoxycholylethylamine ( bis DOCA-NH2) was chemically conjugated to the carboxylic groups of LMWH, 2DS-LMWH, 6DS-LMWH and NDSHbD.…”

Section: Methodsmentioning

confidence: 99%

“…The therapeutic effects of heparin have been mainly attributed to its ability to inhibit the interaction between leukocytes and activated endothelial cells (ECs) and to neutralize inflammatory mediators, such as chemokines and growth factors at the site of inflammation [12–14]. We have shown that 6-O desulfation of lower molecular weight heparin (LMWH) conjugated with deoxycholic acid inhibits transmigration of T cells through activated ECs and inhibits recruitment of T cells into inflamed arthritis tissues [15]. However, the efficacy of desulfation of other sites of LMWH on the anti-inflammatory functions has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

“…A variety of formulation and enhancing strategies to increase oral bioavailability of heparin have been investigated [16–19]. A lipidation strategy which involves conjugation of deoxycholic acid (DOCA) to facilitate its transport through the intestinal epithelium has been successfully applied to desulfated LMWH in our previous reports [15, 20]. Thus, identification of modified LMWHs that exert higher anti-inflammatory efficacy as well as lower anti-coagulant activity offers not only an insight into the mechanisms of heparin action, but also significant potential for development of oral agents.…”

Section: Introductionmentioning

confidence: 99%

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Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

Faruque¹,

Kang²,

Hwang³

et al. 2017

PLoS ONE

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Identification of the structure-function relationship of heparin, particularly between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory activities, is critical in order to evaluate the biological effects of heparin, especially in conjunction with modifications for oral formulation. In this study, we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic modifications have differential effects on the blocking of interactions between sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore, 6DSHbD coated on the apical surface of inflamed endothelium directly blocked the adhesive interactions of circulating T cells, which was confirmed in vivo by suppressing T cell adhesion at post-capillary venular endothelium. Thus, in series with our previous study demonstrating inhibition of transendothelial migration, oral delivery of low anticoagulant LMWH to venular endothelium of inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell recruitment and provides a rationale for the development of modified oral heparins as innovative agents for the treatment of chronic inflammatory arthritis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

Faruque¹,

Kang²,

Hwang³

et al. 2017

PLoS ONE

Self Cite

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“…We also recently demonstrated that a non-anticoagulant fraction of heparin, O-desulfated heparin, can inhibit leukocyte infiltration in vivo via an effect on platelet/leukocyte interactions (Riffo-Vasquez et al, 2015). Furthermore, recent data in mice demonstrated that bis-deoxycholic acid conjugated to a 6-O-desulfated LMWH was internalized into endothelial cells and that this intracellular modified heparin was able to inhibit the transendothelial recruitment of T cells via inhibition of a Rho-Adependent mechanism (Kang et al, 2014).…”

Section: B Inflammatory Cellular Adhesion and Traffickingmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Move to Nano‐Arthrology: Targeted Stimuli‐Responsive Nanomedicines Combat Adaptive Treatment Tolerance (ATT) of Rheumatoid Arthritis

Liu

Guo

Liang

2018

Biotechnology Journal

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Rheumatoid arthritis (RA) is one of the most popular chronic autoimmune diseases characterized with persistent synovial inflammation and bone destruction. Although considerable developments have been gained in clinical treatment of RA, the major drawback to RA therapy stems from the adaptive treatment tolerance (ATT) following the long-term drug use, which causes compromised efficacy, sustained drug dose increase, and severe adverse events. To address these challenges, it is of great significance to put forward innovative therapeutic approaches for RA treatment. Nowadays, developments of nanotechnology-based nanomedicines (NMs) for RA are in progress. Multifunctional NMs with targeted stimuli-responsive features have been one of the central concepts in designing more accessible formulations for efficient RA treatment. These NMs are able to postpone RA progression effectively, because of their delivery and on-demand release of medicaments at targeted sites in response to external or internal stimuli related to the RA pathophysiology without obvious adverse side-effects on the normal tissues. Therefore, NMs have gained interest from pre-clinical research scientists as well as clinical doctors worldwide. Herein, the authors highlight the recent attempts of targeted stimuli-responsive NMs for RA therapy in the last 5 years. The described progresses may pave the way to novel and highly effective RA NMs.

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Intracellular delivery of desulfated heparin with bile acid conjugation alleviates T cell-mediated inflammatory arthritis via inhibition of RhoA-dependent transcellular diapedesis

Cited by 8 publications

References 43 publications

Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

Pharmacology of Heparin and Related Drugs

Move to Nano‐Arthrology: Targeted Stimuli‐Responsive Nanomedicines Combat Adaptive Treatment Tolerance (ATT) of Rheumatoid Arthritis

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