One specific way to overcome the side effects of cancer chemotherapy and to achieve improved therapeutic effects in the treatment of cancer is to develop drug delivery systems that enhance tumor cytotoxicity and cellular entry. Dendrimers, due to their controllable size and monodispersity, can act as excellent carriers for a wide range of molecules, which can be encapsulated in the interior of the dendrimer or interact with the dendrimer’s terminal groups. Since dendrimers are synthesized from branched monomer units in a stepwise manner, it is possible to conduct a precise control on molecule size, shape, dimension, density, polarity, and solubility by choosing different branching units and surface functional groups. Cardiotonic steroids have long been and continue to be used in the treatment of congestive heart failure as positive inotropic agents. Epidemiological studies had shown that digitalis has also anti-cancer effects. Over the last 10 years, interest in developing cardiotonic steroids as anti-cancer agents has grown progressively. The studies on the structure–activity relationship revealed that lactone in position 17β is crucial for the cardiotoxicity of digoxin and proscillaridin A. Therefore, we synthesized two compounds Dig and Prosc, derivatives of these glycosides containing the carboxylic group instead of the lactone moiety. In the present study Dig and Prosc were conjugated to G3 PAMAM dendrimers (with 32 primary amino groups on surface) via amide linkage. Our previous experimental studies have demonstrated that these compounds treatment prevented the growth and decreased the number of viable cells in both estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 breast cancer cells. To test whether cytotoxic properties were related to DNA-binding and topoisomerases action, these conjugates were evaluated in a cell-free system. While the parent drug - Dig inhibited only topoisomerase II at concentration 100 nM, PAMAM-Dig conjugate inhibited both topoisomerase II at lower 30 nM concentration and additionally – inhibited topoisomerase I at the same 30 nM concentration. Prosc – as a parent drug was a potent poison of topoisomerase I and II at 100 nM and 30 nM, respectively, whereas PAMAM-Prosc inhibited either topoisomerase I and II at lower concentration of 30 nM. These studies suggest that the conjugation of modified glycosides Dig and Prosc with G3 PAMAM-NH₂ significantly improved the ability of parent compounds to inhibition of DNA topoisomerases. It seems to be very important, because poisoning of topoisomerases is frequently associated with apoptosis and the level of topoisomerases in cancer cells are generally higher than in normal ones. Therefore, drugs able to interact with both DNA topoisomerase types may show selectivity for cancer cells.

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