Prevention effect of orally active heparin conjugate on cancer-associated thrombosis

Taslim A. Al-Hilal, Farzana Alam, Jin Woo Park, Kwang Meyung Kim, Ick Chan Kwon, Gyu Ha Ryu, Youngro Byun

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62 ± 0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.

Original languageEnglish
Pages (from-to)155-161
Number of pages7
JournalJournal of Controlled Release
Volume195
DOIs
Publication statusPublished - 2014 Dec 10
Externally publishedYes

Fingerprint

Heparin
Thrombosis
Low Molecular Weight Heparin
Neoplasms
Inbred ICR Mouse
Factor Xa
Tropism
Deoxycholic Acid
Subcutaneous Injections
Fibrin
Bile Acids and Salts
Thrombocytopenia
Fibrinogen
Oral Administration
Hot Temperature
Hemorrhage
Morbidity
Mortality
Liver
Therapeutics

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Prevention effect of orally active heparin conjugate on cancer-associated thrombosis. / Al-Hilal, Taslim A.; Alam, Farzana; Park, Jin Woo; Kim, Kwang Meyung; Kwon, Ick Chan; Ryu, Gyu Ha; Byun, Youngro.

In: Journal of Controlled Release, Vol. 195, 10.12.2014, p. 155-161.

Research output: Contribution to journalArticle

Al-Hilal, Taslim A. ; Alam, Farzana ; Park, Jin Woo ; Kim, Kwang Meyung ; Kwon, Ick Chan ; Ryu, Gyu Ha ; Byun, Youngro. / Prevention effect of orally active heparin conjugate on cancer-associated thrombosis. In: Journal of Controlled Release. 2014 ; Vol. 195. pp. 155-161.
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