Enhanced drug toxicity by conjugation of platinum drugs to polymers with guanidine containing zwitterionic functional groups that mimic cell-penetrating peptides

Inspired by the Ringsdorf model, statistical copolymers with solubility enhancers, platinum drugs and groove binders were compared. In addition, the polymer was furnished with a cell penetrating moiety using a guanidine containing polymer. A block copolymer based on poly(4-vinylbenzyl chloride) and a block carrying zwitterionic monomer prepared from arginine was obtained using RAFT polymerization. Thiol–chloride reaction was then employed to attach thioglycerol (TG) as the water-soluble functional group, 9-aminoacridine (AA) as groove binder to enhance DNA binding and reactive diamino functionality as the bidentate ligand for the conjugation of platinum drugs. The aim of this work was to create a stable bond between the polymer and the drug to answer the question if it is essential to have degradable linkers to generate high drug activity. Three platinated polymers – having only the solubility enhancer, the solubility enhancer and the groove binder and with all three moieties – were compared in regards to their ability to enter the human ovarian carcinoma A2780 cells. Unsurprisingly, the zwitterionic polymer showed the highest uptake, which also coincided with a higher toxicity of the drug. Conjugated to the zwitterionic polymer, the platinum drug showed a higher toxicity than free cisplatin. In summary, even 40 years after the concepts was first established by Ringsdorf, this design still seems to have high validity highlighting that the suitable polymer design can enhance the activity of the drug.