N. R. Kuznetsovaa, E. V. Svirshchevskayaa, N. S. Sitnikovb, L. Abodoc, H. Sutoriusc, J. Zapked, J. Veldere, P. Thomopouloue, H. Oschkinatd, A. Prokopc, H.-G. Schmalze, A. Yu. Fedorovb, E. L. Vodovozovaa, #

#Phone: +7 (495) 330-66-10; fax: +7 (495) 330-66-01; e-mail:

aShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str. 16/10, Moscow, 117997 Russia;
bDepartment of Organic Chemistry, Chemical Faculty, N.I.Lobachevsky Nizhny Novgorod State University, Nizhny Novgorod, Russia;
cDepartment of Oncology/Hematology, Childrens Hospitel Cologne, Köln, Germany;
dLeibniz-Institute of Molecular Pharmacology (FMP), Berlin, Germany;
eDepartment für Chemie, Universität zu Köln, Köln, Germany

Abstract. Colchicine site binders blockers of tubulin polymerization are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable formulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine yeast phosphatidylinositol palmitic or oleic prodrug, 8 : 1 : 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleic bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals.

Keywords: liposomes, colchicinoids, lipophilic prodrugs, fatty acid esters, anti-proliferative activity, proapoptotic activity.

. 2013, 39 (5): 609-618