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 language | English |
|---|---|
| Pages (from-to) | 155-161 |
| Number of pages | 7 |
| Journal | Journal of Controlled Release |
| Volume | 195 |
| DOIs | |
| Publication status | Published - 2014 Dec 10 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Prevention effect of orally active heparin conjugate on cancer-associated thrombosis
AU - Al-Hilal, Taslim A.
AU - Alam, Farzana
AU - Park, Jin Woo
AU - Kim, Kwang Meyung
AU - Kwon, Ick Chan
AU - Ryu, Gyu Ha
AU - Byun, Youngro
PY - 2014/12/10
Y1 - 2014/12/10
N2 - 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.
AB - 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.
KW - Anticoagulants
KW - Cancer-associated thrombosis
KW - Heparin conjugate
KW - Oral delivery
UR - http://www.scopus.com/inward/record.url?scp=84908590374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84908590374&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2014.05.027
DO - 10.1016/j.jconrel.2014.05.027
M3 - Article
C2 - 24862320
AN - SCOPUS:84908590374
VL - 195
SP - 155
EP - 161
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -