Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid

Farzana Alam, Taslim A. Al-Hilal, Seung Woo Chung, Donghyun Seo, Foyez Mahmud, Hansung Kim, Sang Yoon Kim, Youngro Byun

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight heparin derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3±2.89%) and prolonged the mean residence time (7.5±0.5h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. Invitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2±3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth invivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.

Original languageEnglish
Pages (from-to)6543-6552
Number of pages10
JournalBiomaterials
Volume35
Issue number24
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Deoxycholic Acid
Angiogenesis Inhibitors
Complexation
Heparin
Tumors
Acids
Neoplasms
Biological Availability
Taurocholic Acid
Oncology
Angiography
Low Molecular Weight Heparin
Blood vessels
Transcytosis
X-Ray Microtomography
Vascular Endothelial Growth Factor A
Sodium
Molecular weight
Intestines
Blood Vessels

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Alam, Farzana ; Al-Hilal, Taslim A. ; Chung, Seung Woo ; Seo, Donghyun ; Mahmud, Foyez ; Kim, Hansung ; Kim, Sang Yoon ; Byun, Youngro. / Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid. In: Biomaterials. 2014 ; Vol. 35, No. 24. pp. 6543-6552.
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abstract = "Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight heparin derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3±2.89{\%}) and prolonged the mean residence time (7.5±0.5h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. Invitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2±3.9{\%}), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth invivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.",
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Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid. / Alam, Farzana; Al-Hilal, Taslim A.; Chung, Seung Woo; Seo, Donghyun; Mahmud, Foyez; Kim, Hansung; Kim, Sang Yoon; Byun, Youngro.

In: Biomaterials, Vol. 35, No. 24, 01.01.2014, p. 6543-6552.

Research output: Contribution to journalArticle

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AU - Alam, Farzana

AU - Al-Hilal, Taslim A.

AU - Chung, Seung Woo

AU - Seo, Donghyun

AU - Mahmud, Foyez

AU - Kim, Hansung

AU - Kim, Sang Yoon

AU - Byun, Youngro

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