Anti-cancer therapeutic agents exert their effect by causing DNA damage and subsequent induction of apoptosis. Copper-complexes are known to irreversibly modify nucleic acids and have received considerable attention because of their potential applications as chemotherapeutic agents. However, their selective and safer delivery is still a challenge. Nanoparticle mediated delivery of therapeutics has blossomed in recent years, and the potential applications are far reaching. Herein we describe a novel therapeutic strategy for delivering effective doses of DNA-cleaving agents by a defined self-assembled polymeric nanoarchitecture,To achieve this goal, a novel copper phenanthroline (Cu-Phen-NH2) complex was synthesized. X-ray analyses of single crystals showed that the cupric complexes of two phenanthroline molecules were able to adopt dimeric helical geometries with L2Cu2 stoichiometries in the solid state. For drug loading, both covalent and non-covalent (entrapment) strategies were adopted. Our non-covalent approach followed a co-self-assembly of amphiphilic PS-b-PAA and polyethylene glycol cetyl ether in presence of Cu-Phen-NH2. Solvent evaporation method was used to generate particles with and without the Cu-Phen-NH2, while covalent conjugation as was performed by carbodiimide mediated coupling. The hydrodynamic diameter of these particles was significantly different from blank nanoparticles. The in vitro properties of nanoparticles conjugated to or co-assembled with this novel ternary copper(II) phenanthroline complex (Cu-Phen) were investigated, and their ability to bind and cleave DNA under protic conditions was determined. UV-Vis spectroscopic studies revealed the binding capability of Cu-Phen with the DNA. DNA cleavage studies indicated that Cu-Phen was able to effectively cleave plasmid pBR322 DNA in the presence of H2O2 and ascorbic acid, as evident from gel electrophoresis assay. In vitro studies further confirmed an efficient nano-delivery of Cu-Phen complexes and indicated their capability to mediate oxidative damage to nucleobases and/or to the 2-deoxyribose moiety. Detailed physicochemical characterization and their biological studies will be presented in this talk.

Selective amplification and a highly efficient nanoparticle-mediated delivery of DNA-cleaving agents

248th National Meeting (2014)

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