title: Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: biological effects on human tumor cells.
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 oleoyl 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.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia.
authors.forename: N R
authors.initials: NR
authors.lastname: Kuznetsova
authors.forename: E V
authors.initials: EV
authors.lastname: Svirshchevskaya
authors.forename: N S
authors.initials: NS
authors.lastname: Sitnikov
authors.forename: L
authors.initials: L
authors.lastname: Abodo
authors.forename: H
authors.initials: H
authors.lastname: Sutorius
authors.forename: J
authors.initials: J
authors.lastname: Zapke
authors.forename: J
authors.initials: J
authors.lastname: Velder
authors.forename: P
authors.initials: P
authors.lastname: Thomopoulou
authors.forename: H
authors.initials: H
authors.lastname: Oschkinat
authors.forename: A
authors.initials: A
authors.lastname: Prokop
authors.forename: H G
authors.initials: HG
authors.lastname: Schmalz
authors.forename: A Yu
authors.initials: AY
authors.lastname: Fedorov
authors.forename: E L
authors.initials: EL
authors.lastname: Vodovozova
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D005227:Fatty Acids / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D014230:Triazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D014404:Tubulin / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D008081:Liposomes; D011355:Prodrugs; D014230:Triazoles; D014404:Tubulin; D003078:Colchicine