Suppression of angiogenesis and tumor growth by orally active deoxycholic acid-heparin conjugate.

Heparin, a potent inhibitor of blood coagulation, exhibits antitumoral action in tumor progression such as in angiogenesis and metastasis but is not orally absorbed in the body, making it an attractive candidate as an oral drug for antiangiogenic cancer therapy. We generated LHD or orally active heparin using low molecular weight heparin (LMWH) and deoxycholic acid that is effectively absorbed in the gastrointestinal tract. Using the in vitro endothelial tubular formation and chicken chorioallantoic membrane angiogenesis assay, we found that antiangiogenic activity of this LHD was similar to that of LMWH. From the in vivo Matrigel plugs assay, LHD treated orally could effectively inhibit angiogenesis into the plugs induced by basic fibroblast growth factor, whereas LMWH treated orally could not due to no oral absorption. In addition, when this LHD was orally administered into the tumor bearing mice, it significantly inhibited tumor growth by its antiangiogenic therapeutic mechanism, and when accompanied with doxorubicin, it appeared to have an additive effect. Collectively, LHD having antiangiogenic activity could be orally absorbable and inhibit tumor growth via inhibiting angiogenesis. These findings demonstrate the therapeutic potential of LHD in the clinical trials, which is suggested as a new oral therapeutic remedy for cancer therapy.

Antiangiogenic and apoptotic properties of a novel amphiphilic folate-heparin-lithocholate derivative having cellular internality for cancer therapy.

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.

In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implications.

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors--(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.