Heparin, a potent
anticoagulant used for the prevention of
venous thromboembolism, has been recognized as a
tumor angiogenesis inhibitor. Its limitation in clinical application for
cancer therapy, however, arises from its strong
anticoagulant activity, which causes associated adverse effects. In this study, we show the structural correlation of LHT7, a previously developed
heparin-based
angiogenesis inhibitor, with its influence on
VEGF blockade and its decreased
anticoagulant activity. LHT7 was characterized as having average seven molecules of
sodium taurocholates conjugated to one molecule of
low-molecular-weight heparin (
LMWH). This study showed that the conjugation of
sodium taurocholates selectively blocked interaction with
antithrombin III (ATIII) while enhancing the binding with
VEGF. This resulted in LHT7 to have negligible
anticoagulant activity but potent anti-angiogenic activity. Following up on this finding, we showed that the bidirectional effect of
sodium taurocholate conjugation was due to its unique structure, that is, the sterane core hindering the ATIII-binding pentasaccharide unit of
LMWH with its bulky and rigid structural characteristics while the terminal
sulfate group interacts with
VEGF to produce stronger binding. In addition, we showed that LHT7 was localized in the
tumor, especially on the endothelial cells. One explanation for this might be that LHT7 was delivered to the
tumor via platelets.