1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences 2. N.I. Lobachevsky Nizhny Novgorod State University 3. G.A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences 4. Department of Chemistry, M.V. Lomonosov Moscow State University 5. UMR-CNRS 6264, Saint Jerome Department of Sciences, Aix-Marseille University 1 and 2
Abstract: The antimitotic agent combretastatin A4 (СА-4) has been suggested as an antivascular agent for anticancer therapy relatively recently. To reduce systemic toxicity by means of administration in liposome formulations, in this study new lipophilic prodrugs, oleic derivatives of СА-4 and its 4-arylcoumarin analog (СА4-Ole and ArC-Ole, respectively), have been synthesized: Liposomes of 100 nm mean diameter prepared on the basis of egg phosphatidylcholine and phosphatidylinositol from bakers yeast have been shown to include completely up to 10 mol. % of СА4-Ole, or 7 mol. % of ArC-Ole. Also, prodrug bearing liposomes decorated with tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been constructed to achieve targeting to endothelium under neovascularization. The antitumor activity in vivo was studied in the model of slowly growing mouse breast cancer. Under the used dose (22 mg/kg) as well as the regimen of treatment (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect, and oppositely even stimulated tumor growth. Liposome formulations of CA4-Ole did not show such stimulation. However, to achieve pronounced antitumor effect, number of injections of liposomes should be apparently elevated. New antimitotic agent ArC revealed cytotoxic activity of only one tenth value obtained for CA-4 in vitro in the culture of human breast carcinoma cells. Nevertheless, in vivo in the mouse model of breast cancer this compound showed antitumor effect under double СА-4 equivalent dose. The results demonstrate availability of SiaLeX-liposomes loaded with ArC-Ole: this preparation began to inhibit tumor growth already after the second injection. It is necessary further to choose doses and regimens of administration both for ArC and liposome formulations bearing ArC-Ole.
Reference: Moiseeva E.V., Kuznetsova N.R., Svirshchevskaya E.V., Bovin N.V., Sitnikov N.S., Shavyrin A.S., Beletskaya I.P., Combes S., Fedorov A.Yu., Vodovozova E.L., Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer, Biomeditsinskaya khimiya, 2012, vol: