Antiangiogenic and Apoptotic Properties of a Novel Amphiphilic Folate-Heparin-Lithocholate Derivative Having Cellular Internality for Cancer Therapy

Abstract

Purpose. 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. Materials and 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.

Tumor Endothelial Cell Targeted Cyclic RGD-modified Heparin Derivative: Inhibition of Angiogenesis and Tumor Growth

“…Anhydrous formamide, and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC) were obtained from Sigma Chemical Co. (St. Louis, MO, USA). N-(2-aminoethyl)-lithocholylamide (LCA-NH 2 ) was prepared as described in the previous report (24,27). RGD-bearing synthetic peptide (cRGDyK, cyclic Arg-Gly-Asp-D-Tyr-Lys) was the product of FutureChem Co. Ltd. (Seoul, Korea).…”

“…Recently, we have developed low anticoagulant bile acid acylated heparin derivatives (24)(25)(26)(27) to overcome side effects such as hemorrhage, HIT (heparin-induced thrombocytopenia) (28) and osteoporosis (29) that are caused by the strong anticoagulant activity of heparin when heparin is used at high dosages and for extended periods of time. Other research groups have also developed chemically modified heparin derivatives including carboxyl-reduced heparin, N-O-desulphated/N-resulphated heparin, N-desulphated/N-reacetylated heparin (30), heparin-steroid conjugate (31), heparin-carrying polystyrene (32), and neoheparin (33).…”

“…These chemically modified heparin derivatives have advantages that reduce the risk of hemorrhage, and prevent metastasis, angiogenesis, and tumor growth. Among them, bile acid-acylated heparin derivatives effectively prevented proliferation of tumor and endothelial cells (25), and further showed potent antiangiogenic effect in vitro and in vivo (26,27), thereby exerting similar or superior antitumor effect at much lower doses than heparin or other heparin derivatives. In addition, bile acid heparin derivatives are safe with respect to long-term treatment in a mouse model (25).…”

Polyproline‐type helical‐structured low‐molecular weight heparin (LMWH)‐taurocholate conjugate as a new angiogenesis inhibitor

“…[19][20][21][22][23] Those chemically modified heparin conjugates have an advantage in decreasing the risk of bleeding, as well as enhancing other biological activities of heparin, which prevents angiogenesis, metastasis and cell proliferations. In particular, bile acid-acylated heparin derivatives showed higher anticancer effects than heparin alone due to their carrier effect based on EPR effects, antiangiogenic activities and cell internalized apoptotic effects.…”

“…In particular, bile acid-acylated heparin derivatives showed higher anticancer effects than heparin alone due to their carrier effect based on EPR effects, antiangiogenic activities and cell internalized apoptotic effects. [20][21][22] On the basis of previous studies about bile acid-acylated heparin derivatives, new low-molecular heparin (LMWH)-taurocholate derivatives (LHT) were prepared to make covalent bonding between the amine group of N-taurocholylethylenediamine (TCA-NH 2 ) and carboxylic acids in the LMWH via amide formations. The LHT derivatives, we have developed for this study have, an academic novelty since these conjugates have quite different prop-erties compared with other previous heparin derivatives.…”