Drug resistance is a multifactorial phenomenon that limits the action of antibiotics and chemotherapeutics, thus making urgent the development of new therapeutic strategies capable of inducing cytotoxic effects circumventing chemoresistance. Natural and synthetic cationic peptides and polymers has given satisfactory results both in microbiology, as antibacterial agents, and in the oncological field, resulting effective against several tumors, including human neuroblastoma (NB) [1,2]. To this end, we synthetized, characterized, and tested on etoposide-sensitive (HTLA-230) and-resistant (HTLA-ER) human NB cells , two ammonium chloride polystyrene-based copolymers P5 and P7. Both copolymers were water-soluble, showed a positive surface charge, due to nitrogen atoms which resulted protonated in the whole physiological pH range, and showed values of Z-potential favorable to stability in solution . P5 and P7 exhibited excellent buffer capacity, useful to escape lysosome deactivation once inside cells, nanosized particles and were able to reduce NB cell viability in a concentration-dependent way . Interestingly, a significant increase in reactive oxygen species (ROS) production was observed in both NB cell populations treated with P5 or P7 establishing, for both copolymers, an unequivocal correlation between cytotoxicity and ROS generation . Unexpectedly, the ROS-related cytotoxic effects of both copolymers were even higher on HTLA-ER cells, thus proving that P5 and P7 could be promising template macromolecules for the development of new chemotherapeutic agents able to fight NB chemoresistance .  L.T. Eliassen, et al. Int. J. Cancer. 2006, 119, 493–500.  J. Tan, et al. Biomat. 2020, 252, 120078.  R. Colla, et al. Oncotarget 2016, 7, 70715-70737.  S. Alfei, et al. Nanomaterials 2021, 11, 977.
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