Design and therapeutic evaluation of heparin based bioconjugate for oral delivery and antiangiogenic therapy : 경구전달 및 신생혈관생성 억제 항암효과를 위한 헤파린 유도체의 설계 및 활성 평가

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약학대학 약학과
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서울대학교 대학원
학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과 약제과학전공, 2016. 2. 변영로.
Bioconjugate techniques have been improved with the growth of the bio-pharmaceutical industry. Highly functional biomaterials were modified by various chemical and biological methods for drug delivery and development. Therapeutic agents including carbohydrate, gene, peptide, protein and drug have been improved as a new pharmaceutical composition which is finally applied to human. Among therapeutic polysaccharides, heparin is the one of the unique biomimetic molecules which has potentials of an effective and safe drug.
Heparin is a highly sulfated and linear polysaccharide which is clinically used as an anticoagulant. However, the low bioavailablity of heparin has restricted wide use of it. Heparin and LMWHs have been the drug of choice for the treatment or the prevention of thromboembolic diseases, in other way, their uses were limited by parenteral injection. To overcome this problem, tetraDOCA was conjugated at the end of heparin via chemical glycation. This conjugation increased the bioavailability of low molecular weight heparin named enoxaparin, and it showed therapeutic effects in DVT and bleeding animal models. In addition, we designed heparin based orally available nanocomplex using heparin, bile acid and protamine. Positively charged protamine could form a stable nanocomplex with heparin and other polysaccharides through electrostatic interactions. The study about oral delivery using bile acids and heparin basd nanocomplex indicated that the macromolecule could be delivered by interacting with ASBT in the ileum.
In other way, it has been known that heparin and heparin conjugates can inhibit tumor activity by interacting with tumor related to proteins such as VEGF and bFGF. But the use of LMWH for tumor inhibition effect has been limited because heparin is a strong anticoagulant. To expand the clinical use of heparin and heparin derivatives, in this study, LMWH was conjugated with highly functional fragments that have a binding affinity to the heparin-binding site. The chemical conjugate of LMWH and suramin fragments showed tumor inhibition effect on various experiments including VEGF-mediated HUVEC assay. In addition, orally available heparin fragment-deoxyholic acid conjugates were designed to confirm the size related the effects of heparin. Heparin fragment-deoxycholic acid conjugates were also able to have cancer effects by inhibiting the angiogenic activity of growth factors depending on its molecular size. When we use highly functional heparin conjugates such heparin-suramine or heparin fragment-deoxycholic acid conjugates, PEG-protamine based nanocomplex could be an attractive approach to optimize the therapeutic effect and delivery of heparin conjugates. PEG-protamine could increase the targeting effect of heparin-suramin conjugate with increased anticancer effect. PEG-protamine nanocomplex showed potentials for a novel drug carrier for functional anticancer polysaccharides. Finally, the study about the oral delivery and antiangiogeneic effects of heparin conjugates would open a new prospect in the field of drug development and delivery.
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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