Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid
- Authors
- Alam, Farzana; Al-Hilal, Taslim A.; Chung, Seung Woo; Seo, Donghyun; Mahmud, Foyez; Kim, Han Sung; Kim, Sang Yoon; Byun, Youngro
- Issue Date
- 2014-08
- Publisher
- ELSEVIER SCI LTD
- Citation
- BIOMATERIALS, v.35, no.24, pp.6543 - 6552
- 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 +/- 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, 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 in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor. (C) 2014 Elsevier Ltd. All rights reserved.
- Keywords
- MOLECULAR-WEIGHT HEPARIN; BILE-ACID; MICROCOMPUTED TOMOGRAPHY; CATIONIC ANALOG; TRANSPORTERS; CARRIER; ABSORPTION; RESISTANCE; DISCOVERY; THERAPY; MOLECULAR-WEIGHT HEPARIN; BILE-ACID; MICROCOMPUTED TOMOGRAPHY; CATIONIC ANALOG; TRANSPORTERS; CARRIER; ABSORPTION; RESISTANCE; DISCOVERY; THERAPY; Heparin conjugate; Deoxycholic acid; Angiogenesis inhibitor; Oral delivery
- ISSN
- 0142-9612
- URI
- https://pubs.kist.re.kr/handle/201004/126547
- DOI
- 10.1016/j.biomaterials.2014.04.050
- Appears in Collections:
- KIST Article > 2014
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