title: Biological evaluation of polymeric micelles with covalently bound doxorubicin.
abstract: The main limitation of contemporary anticancer chemotherapy remains to be the insufficient specificity of the drugs for tumor tissue, which decreases the maximum tolerated dose due to severe side effects. Micellar drug delivery systems based on amphiphilic block copolymers with a very narrow size distribution (10 to 100 nm in diameter) is a novel innovative approach. Here, we report biological and pharmacological properties of polymeric micellar conjugate containing doxorubicin (DOX) covalently bound via hydrolytically cleavable hydrazone bonds to the micelle core. The system had a very low systemic toxicity (almost 20 times lower than free DOX) and long circulation in the bloodstream (with half of the dose after 24 h). Significant accumulation of tested micelles within the tumor was confirmed by fluorescent whole body imaging. Our new micellar system showed promising therapeutic activity against established murine EL-4 T-cell lymphoma; it was found that it is able to completely cure about 75% of tumor-bearing mice (with doses of either 1 x 150 mg DOX kg(-1) or 2 x 75 mg DOX kg(-1), administered i.v.). Moreover, treatment with micelles in cured mice induced tumor-specific resistance. Up to 80% of these mice survived rechallenge with original but not with distinct tumor cells.
authors.affiliation: Institute of Microbiology AS CR, v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic. vetvicka@biomed.cas.cz
authors.forename: David
authors.initials: D
authors.lastname: Vetvicka
authors.forename: Martin
authors.initials: M
authors.lastname: Hruby
authors.forename: Ondrej
authors.initials: O
authors.lastname: Hovorka
authors.forename: Tomas
authors.initials: T
authors.lastname: Etrych
authors.forename: Miroslav
authors.initials: M
authors.lastname: Vetrik
authors.forename: Lubomir
authors.initials: L
authors.lastname: Kovar
authors.forename: Marek
authors.initials: M
authors.lastname: Kovar
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Blanka
authors.initials: B
authors.lastname: Rihova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D006207:Half-Life; D006835:Hydrazones; D006868:Hydrolysis; D016399:Lymphoma, T-Cell / Q000188:drug therapy; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin