| 초록 |
Heparin, highly sulphated HSGAGs, has been studied as an antitumor agent. Recently, Several chemically modified heparins with low anticoagulant activity have been suggested for the prevention of tumor growth. In this study, hydrophobically modified unfractionated heparins (Mw 12,000) were developed by the covalent attachment with lithocholic acids and were evaluated its antitumor effect in C3H/HeN mice bearing SCC7 cells. Three heparin-lithocholic acid conjugates (HL) were synthesized by controlling feed mole ratio of EDCA. Each HL contained 8.6, 10.5, 11.4 of lithocholic acids, indicated by degree of substitution (DS), formed self-aggregates in the aqueous phase by amphiphilic property, and showed about 160-170nm in size. Anticoagulant activity of HL retained 70, 38, and 10%, respectively, with increase in the DS. Also, their zeta-potential values decreased to ~ -50mV, when compared with the UFH (-75~-100mV). With the developed HL, we investigated pharmacokinetic parameters, half-life (t1/2), volume of distribution (Vd), and clearance (CL), in Sprague-Dawley rat model. Due to the hydrophobic modification, the plasma half-life was significantly enhanced. Moreover, the assessment of Gamma scintigraphy images of I131-HL-Tyr in SCC7 tumor bearing mice exhibited increased tumor localization at 24h post-injection. In the Brdu analysis, cell proliferation Inhibition effect was greatly enhanced against SCC7 cells and HUVEC cells by HL, but not UFH. In vivo evaluation for the tumor regression also demonstrated delayed tumor growth in the HL treated mice. These results provide that the attachment of an appropriate number of lithocholic acids to the heparin can facilitate tumor localization and retard tumor growth effectively than the use of only UFH. |
