title: Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin.
abstract: Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Cheng
authors.forename: Fatima Zohra
authors.initials: FZ
authors.lastname: Dahmani
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D049628:Body Size / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005260:Female; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007275:Injections, Intravenous; D007797:Laminin / Q000737:chemistry; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010316:Particle Size; D011509:Proteoglycans / Q000737:chemistry; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014315:Triterpenes / Q000737:chemistry*; D047368:Tumor Burden / Q000187:drug effects; D000097245:Ursolic Acid
chemical_list: D020533:Angiogenesis Inhibitors; D000925:Anticoagulants; D003094:Collagen; D004338:Drug Combinations; D006001:Glycoconjugates; D006495:Heparin, Low-Molecular-Weight; D007797:Laminin; D008823:Micelles; D011509:Proteoglycans; D013501:Surface-Active Agents; D014315:Triterpenes; D000097245:Ursolic Acid; C059485:matrigel