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 32P-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.
Highlights
Ellipticine (5,11-dimethyl-6H-pyrido(4,3-b)carbazole) and its derivatives are efficient anticancer compounds that function through multiple mechanisms participating in cell cycle arrest and initiation of apoptosis
The levels of ellipticine-DNA adducts formed in rat tissues after their administration with ellipticine-micelles were one order of magnitude lower in most organs than in those of rats treated with free ellipticine (p < 0.001, different from levels of ellipticine-derived DNA adducts formed by free ellipticine; comparison was performed by t-test analysis), with an exception of brain, where levels of ellipticine-DNA adducts formed by administration of rats with ellipticine-micelles were higher than in DNA of brain of rats treated with free ellipticine (0.05 ± 0.01 and 0.35 ± 0.03 adducts per 108 normal deoxyribonucleotides in brain DNA of rats treated with 10 mg of free ellipticine and ellipticine in micelles, respectively)
The results demonstrate that treatment of rats with free ellipticine or this anticancer agent in micelles resulted in formation of ellipticine-derived
Summary
Ellipticine (5,11-dimethyl-6H-pyrido(4,3-b)carbazole) and its derivatives are efficient anticancer compounds that function through multiple mechanisms participating in cell cycle arrest and initiation of apoptosis (for a summary see [1,2,3,4,5,6]). We utilized a micellar form of ellipticine to study a comparison between the biodistribution of this drug form and free ellipticine to reach the tissues in which the formation of covalent ellipticine-derived DNA adducts are generated. The formation of ellipticine-derived DNA adducts as the biological end-point of the pharmacological and genotoxic effects of this drug, mediated by free ellipticine and its micellar form, measured with the 32P-postlabeling assay as the imaging method [1,2,3,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24], were employed to determine their biodistribution in rats in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
