Antiangiogenic and apoptotic properties of a novel amphiphilic folate-heparin-lithocholate derivative having cellular internality for cancer therapy.
OBJECTIVE
Anitangiogenic and apoptotic properties of a novel chemically modified heparin derivative with low anticoagulant activity were evaluated on the experimental in vitro and in vivo model.


METHODS
Heparin-lithocholate conjugate (HL) was initially synthesized by covalently bonding lithocholate to heparin. Folate-HL conjugate (FHL) was further synthesized by conjugating folate to HL. Antiangiogenic and apoptotic abilities of HL and FHL were characterized in vitro and in vivo experimentations.


RESULTS
Compared to unmodified heparin, both HL and FHL represented a low anticoagulant activity (38 and 28%, respectively). HL and FHL maintained antiangiogenic activity even further modification from the results of Matrigel plugs assay. FHL specifically induced apoptosis on KB cells having highly expressed folate receptor after cellular internalization. Both administered HL and FHL had similar antiangiogenic activity and inhibitory effect on tumor growth in vivo although FHL induced higher apoptosis on tumor tissues.


CONCLUSIONS
In vivo tumor growth inhibition was possibly due to the decrease of vessel density and apoptotic cell death, although antiangiogenic effect of FHL seemed more actively affected on growth inhibition than apoptotic potential in vivo system. Thus, Low anticoagulant FHL having antiangiogenic and apoptotic properties would provide benefits for the development of a new class of anticancer agent.
Yu
Mi Kyung
MK
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, South Korea.
Lee
Dong Yun
DY
Kim
Yoo Shin
YS
Park
Kyeongsoon
K
Park
Soo Ah
SA
Son
Dai Hyun
DH
Lee
Gee Young
GY
Nam
Jong Hee
JH
Kim
Sang Yoon
SY
Kim
In San
IS
Park
Rang Woon
RW
Byun
Youngro
Y
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D004705:Endocytosis; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007797:Laminin; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000517:prevention & control*; D011509:Proteoglycans; D011956:Receptors, Cell Surface / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000925:Anticoagulants; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004338:Drug Combinations; D058973:Folate Receptors, GPI-Anchored; D007797:Laminin; D011509:Proteoglycans; D011956:Receptors, Cell Surface; C519846:folate-heparin-lithocholate; C519845:heparin-lithocholate; C059485:matrigel; D008095:Lithocholic Acid; D006493:Heparin; D003094:Collagen