Cyclic RGDyk-conjugated LMWH-taurocholate derivative as a targeting angiogenesis inhibitor.
LMWH-taurocholate derivative (LHT7) has been reported as a novel angiogenesis inhibitor, due to its ability to bind to several kinds of growth factors, which play critical roles in tumor angiogenesis. In this study, we have highlighted the enhanced antiangiogenic activity of LHT7, by using cyclic RGDyk (cRGD), a targeting moiety that was chemically conjugated to LHT7 via amide bond. The SPR study revealed that cRGD-LHT7 bound to α(v)β(3) integrin as strongly as cRGD, and it bound to VEGF as strongly as LHT7. Importantly, in vitro anti-angiogenesis studies revealed that cRGD-LHT7 had a significant inhibition effect on HUVEC tubular formation. Finally, cRGD-LHT7 showed a greater inhibitory efficiency on the tumor growth in the U87MG xenograft model than the original LHT7, which was owed to its ability to target the tumor cells. All of these findings demonstrated that cRGD-LHT7 targeted α(v)β(3) integrin-positive cancer cells and endothelial cells, resulting in a greater anti-angiogenesis effect on the solid tumors.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Asarasin
A
Adulnirath
Seung Woo
SW
Chung
Jooho
J
Park
Seung Rim
SR
Hwang
Ji-Young
JY
Kim
Victor C
VC
Yang
Sang Yoon
SY
Kim
Hyun Tae
HT
Moon
Youngro
Y
Byun
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; D039302:Integrin alphaVbeta3; C580866:LHT7 compound; D010456:Peptides, Cyclic; C580867:cRGD-LHT7; C507169:cyclic arginine-glycine-aspartic acid peptide; D013656:Taurocholic Acid