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, Han Sung Kim, Sang Yoon Kim, Youngro Byun

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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
Issue number24
Publication statusPublished - 2014 Aug

Bibliographical note

Funding Information:
This study was supported by grants from the Converging Research Center Program (grant no. 2012K-001398 ) and the Bio & Medical Technology Development Program (grant no. 2012028833 ), through the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Education, Science and Technology , and Mediplex Corp., Korea .

All Science Journal Classification (ASJC) codes

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


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