Alam, Farzana Al-Hilal, Taslim A. Chung, Seung Woo Seo, Donghyun Mahmud, Foyez Kim, Han Sung Kim, Sang Yoon Byun, Youngro 2024-01-20T09:05:02Z 2024-01-20T09:05:02Z 2021-09-05 2014-08 0142-9612 https://pubs.kist.re.kr/handle/201004/126547 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. English ELSEVIER SCI LTD MOLECULAR-WEIGHT HEPARIN BILE-ACID MICROCOMPUTED TOMOGRAPHY CATIONIC ANALOG TRANSPORTERS CARRIER ABSORPTION RESISTANCE DISCOVERY THERAPY Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid Article 10.1016/j.biomaterials.2014.04.050 1 BIOMATERIALS, v.35, no.24, pp.6543 - 6552 BIOMATERIALS 35 24 6543 6552 scie scopus 000338804500038 2-s2.0-84901430271 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article MOLECULAR-WEIGHT HEPARIN BILE-ACID MICROCOMPUTED TOMOGRAPHY CATIONIC ANALOG TRANSPORTERS CARRIER ABSORPTION RESISTANCE DISCOVERY THERAPY Heparin conjugate Deoxycholic acid Angiogenesis inhibitor Oral delivery