Liposome formulations of combretastatin A4 and its 4-arylcoumarin analogue prodrugs: The antitumor effect in the mouse model of breast cancer |
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Authors: | E V Moiseeva N R Kuznetsova E V Svirshchevskaya N V Bovin N S Sitnikov A S Shavyrin I P Beletskaya S Combes A Yu Fedorov E L Vodovozova |
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Institution: | 1.Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry,Russian Academy of Sciences,Moscow V-437, GSP,Russia;2.N.I. Lobachevsky Nizhny Novgorod State University,Nizhny Novgorod,Russia;3.G.A. Razuvaev Institute of Organometallic Chemistry,Russian Academy of Sciences,Nizhny Novgorod,Russia;4.Department of Chemistry,M.V. Lomonosov Moscow State University,Moscow,Russia;5.UMR-CNRS 6264, Saint Jerome Department of Sciences,Aix-Marseille University 1 and 2,Marseille, Cedex 20,France |
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Abstract: | The antimitotic agent combretastatin A-4 (CA-4) has been recently proposed as an antivascular agent for anticancer therapy.
In order to reduce systemic toxicity by means of administration in liposome formulations, new lipophilic prodrugs, oleic derivatives
of CA-4 and its 4-arylcoumarin analogue (CA4-Ole and ArC-Ole, respectively), have been synthesized in this study. Liposomes
with mean diameter of 100 nm prepared on the basis of egg phosphatidylcholine and baker’s yeast phosphatidylinositol quantitatively
included up to 15 mol% of CA4-Ole, or 7 mol% of ArC-Ole. To achieve targeting to neovascular endothelium prodrug bearing liposomes
decorated with the tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been also prepared. The antitumor activity
was studied in vivo using the model of slow-growing mouse breast cancer. Under the dose used (22 mg/kg) and the administration
protocol (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal
any anticancer effect; moreover, it even stimulated tumor growth. The liposome formulations of CA4-Ole did not demonstrate
such stimulation. However, to achieve a pronounced antitumor effect, the number of injections of liposomes should be apparently
increased. The cytotoxic activity of a novel antimitotic agent ArC was one order of magnitude lower in the human breast carcinoma
cell culture in vitro. Nevertheless, in vivo in the mouse model of breast cancer the antitumor effect of this compound corresponded
to the double equivalent dose of CA-4. The results demonstrate perspectives of SiaLeX-liposomes loaded with ArC-Ole: the preparation partially inhibited tumor growth already after the second injection. Thus,
subsequent optimization of doses and regimens of administration both for ArC and liposomal ArC-Ole formulations are needed. |
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