Water-soluble galactosamine derivative of β-cyclodextrin as protective ligand and targeted carrier for delivery of toxic anthracycline drug

Abstract

β-cyclodextrin modified with an electron-rich aromatic triazole linker and targeting moiety (galactosamine) was synthesized and studied as a carrier for the anticancer drug, doxorubicin (DOX), with the aim of targeting the pathological cells, reducing the cardiotoxic side effects and increasing the binding of the drug to DNA. The β-cyclodextrins modified with galactosamine (βCDGAL) are non-toxic and highly soluble in aqueous medium compared to the native βCD and βCD modified only with aromatic moiety, such as triazole linker. Molecular modelling and NMR study gave a deeper insight into the ligand structure, providing an explanation for its increased solubility, and the drug-ligand interactions. The triazole linker strengthened the drug binding and introduced pH dependence of the complex stability constants for βCDGAL derivative, as confirmed by the voltammetry measurements. Spectroscopic studies have shown that entrapment of the DOX in βCDGAL cavity reduces the stability constant of the DOX:Fe(III) complex responsible for the production of cardiotoxic reactive oxygen species and additionally supports the binding of the drug to the double strand DNA. The MTT assay and confocal microscopy results showed that despite encapsulation of the drug in the cyclodextrin molecule, its cytotoxic effect on the liver cancer cell line (HepG2) is comparable to that of the free, non-protected drug.