title: Formation of DNA adducts by ellipticine and its micellar form in rats - a comparative study.
abstract: The requirements for early diagnostics as well as effective treatment of cancer diseases have increased the pressure on development of efficient methods for targeted drug delivery as well as imaging of the treatment success. One of the most recent approaches covering the drug delivery aspects is benefitting from the unique properties of nanomaterials. Ellipticine and its derivatives are efficient anticancer compounds that function through multiple mechanisms. Formation of covalent DNA adducts after ellipticine enzymatic activation is one of the most important mechanisms of its pharmacological action. In this study, we investigated whether ellipticine might be released from its micellar (encapsulated) form to generate covalent adducts analogous to those formed by free ellipticine. The (32)P-postlabeling technique was used as a useful imaging method to detect and quantify covalent ellipticine-derived DNA adducts. We compared the efficiencies of free ellipticine and its micellar form (the poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PAGE-PEO) block copolymer, P 119 nanoparticles) to form ellipticine-DNA adducts in rats in vivo. Here, we demonstrate for the first time that treatment of rats with ellipticine in micelles resulted in formation of ellipticine-derived DNA adducts in vivo and suggest that a gradual release of ellipticine from its micellar form might produce the enhanced permeation and retention effect of this ellipticine-micellar delivery system.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128-40 Prague 2, Czech Republic. stiborov@natur.cuni.cz.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128-40 Prague 2, Czech Republic. zumicka@yahoo.com.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Manhartova
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128-40 Prague 2, Czech Republic. hodek@natur.cuni.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613-00 Brno, Czech Republic. vojtech.adam@mendelu.cz.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Adam
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613-00 Brno, Czech Republic. kizek@sci.muni.cz.
authors.forename: Rene
authors.initials: R
authors.lastname: Kizek
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. evafrei@t-online.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism*; D004339:Drug Compounding / Q000379:methods; D004611:Ellipticines / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008823:Micelles; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004611:Ellipticines; D008823:Micelles; C034192:ellipticine