Heparin, an
anticoagulant that is widely used clinically, is also known to bind to several kinds of
proteins through electrostatic interactions because of its polyanionic character. These interactions are mediated by the physicochemical properties of
heparin such as sequence composition, sulfation patterns, charge distribution, overall charge density, and molecular size. Although this electrostatic character mediates its binding to many
proteins related with
tumor progression, thereby providing its antiangiogenic property, the administration of
heparin for treating
cancer is limited in clinical applications due to several drawbacks, such as its low oral absorption, unsatisfactory
therapeutic effects, and strong
anticoagulant activity which induces hemorrhaging. Here, we evaluated novel, orally active,
low molecular weight heparin (
LMWH) derivatives (LHD) conjugated with
deoxycholic acid (
DOCA) that show reduced
anticoagulant activity and enhanced antiangiogenic activity. The chemical conjugate of
LMWH and
DOCA was synthesized by conjugating the
amine group of N-deoxycholylethylamine (EtDOCA) with the carboxylic groups of
heparin at various
DOCA conjugation ratios. The
LMWH-DOCA conjugate series (LHD1, LHD1.5, LHD2, and LHD4) were further formulated with
poloxamer 407 as a solubilizer for
oral administration. An in vitro endothelial tubular formation and in vivo
Matrigel plug assay were performed to verify the antiangiogenic potential of LHD. Finally, we evaluated
tumor growth inhibition of oral LHD administration in a SCC7 model as well as in A549 human
cancer cell lines in a mouse xenograft model. Increasing
DOCA conjugation ratios showed decreased
anticoagulant activity, eventually to zero. LHD could block angiogenesis in the tubular formation assay and the
Matrigel plug assay. In particular,
oral administration of LHD4, which has 4 molecules of
DOCA per mole of
LMWH, inhibited
tumor growth in SCC7 mice model as well as A549 mice xenograft model. LHD4 was orally absorbable, showed minimal
anticoagulant activity and inhibits
tumor growth via antiangiogenesis. These findings demonstrate the therapeutic potential of LHD4 as a new oral anti-
cancer drug.