Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis

Seung Rim Hwang, Dong Hyun Seo, Taslim A. Al-Hilal, Ok Cheol Jeon, Jin Hee Kang, Sung Hyun Kim, Hansung Kim, Young Tae Chang, Young Mo Kang, Victor C. Yang, Youngro Byun

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O-desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2-O- or 6-O-desulfated LMWH with deoxycholic acid (DOCA) or bisDOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine collagen antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3%). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.

Original languageEnglish
Pages (from-to)374-384
Number of pages11
JournalJournal of Controlled Release
Volume163
Issue number3
DOIs
Publication statusPublished - 2012 Nov 10

Fingerprint

Low Molecular Weight Heparin
Arthritis
Deoxycholic Acid
Experimental Arthritis
Bone and Bones
Biological Availability
Rheumatoid Arthritis
Angiogenesis Inhibitors
Sudden Infant Death
Antibodies
Human Umbilical Vein Endothelial Cells
Fibroblast Growth Factor 2
Heparin
Pharmacokinetics
Joints
Therapeutics
Pharmaceutical Preparations
LMWH-DOCA conjugate

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Hwang, Seung Rim ; Seo, Dong Hyun ; Al-Hilal, Taslim A. ; Jeon, Ok Cheol ; Kang, Jin Hee ; Kim, Sung Hyun ; Kim, Hansung ; Chang, Young Tae ; Kang, Young Mo ; Yang, Victor C. ; Byun, Youngro. / Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis. In: Journal of Controlled Release. 2012 ; Vol. 163, No. 3. pp. 374-384.
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abstract = "The regulation of angiogenesis is an interesting area to consider for novel therapeutic approaches to rheumatoid arthritis (RA). Chemically modified heparins have been developed as possible candidates for angiogenesis inhibitor; however, they have a major clinical drawback in exhibiting poor oral bioavailability. Here, orally absorbable O-desulfated low molecular weight heparin (ODS-LMWH) derivatives were newly synthesized by conjugating 2-O- or 6-O-desulfated LMWH with deoxycholic acid (DOCA) or bisDOCA (a dimer of DOCA), and their physicochemical properties, antiangiogenic potency and pharmacokinetic profiles were assessed. After selecting the best candidate among those derivatives, its therapeutic efficacy on arthritis was investigated in a murine collagen antibody-induced arthritis (CAIA) model. ODS-LMWH derivatives significantly inhibited the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) and basic fibroblast growth factor (bFGF)-induced angiogenesis in the Matrigel plug assay. Among all the compounds, 6ODS-LHbD showed the highest oral bioavailability in rats (19.3{\%}). In the CAIA mouse model, 6ODS-LHbD (10 mg/kg, p.o., S.I.D.) significantly inhibited neovascularization in the joint, the increase of hind-paw thickness, and the structural damage in the bone. Therefore, 6ODS-LHbD would be a promising candidate for an orally active drug for the treatment of RA.",
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Orally active desulfated low molecular weight heparin and deoxycholic acid conjugate, 6ODS-LHbD, suppresses neovascularization and bone destruction in arthritis. / Hwang, Seung Rim; Seo, Dong Hyun; Al-Hilal, Taslim A.; Jeon, Ok Cheol; Kang, Jin Hee; Kim, Sung Hyun; Kim, Hansung; Chang, Young Tae; Kang, Young Mo; Yang, Victor C.; Byun, Youngro.

In: Journal of Controlled Release, Vol. 163, No. 3, 10.11.2012, p. 374-384.

Research output: Contribution to journalArticle

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AU - Hwang, Seung Rim

AU - Seo, Dong Hyun

AU - Al-Hilal, Taslim A.

AU - Jeon, Ok Cheol

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AU - Kim, Sung Hyun

AU - Kim, Hansung

AU - Chang, Young Tae

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AU - Yang, Victor C.

AU - Byun, Youngro

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