Designing anticancer polyurea biodendrimers: the role of core-shell charge/hydrophobicity modulation

Cancer is the second most common cause of death worldwide, with its origin in cells abnormal growth. Available chemotherapeutics present major drawbacks, usually associated with high toxicity and poor distribution, with only a small fraction of the drug reaching the tumour site. Nanoparticles, particularly dendrimers, are paving the way to the front line of cancer treatment, primarily for drug and gene delivery, diagnosis, and disease monitoring. In the present work, we demonstrate the intrinsic anticancer activity of two polycationic core-shell PURE biodendrimers, PUREG4-OEI48 and PUREG4-OCEI24, designed as synthetic mimics of anticancer peptides (SMACPs), and evaluate their action against several cancer cell lines. Our findings show that PUREG4-OEI48 disrupts cell membrane integrity, interacts with mitochondria, and induces cell death by promoting apoptosis, as indicated by Annexin V⁺/PI⁺ cells when incubated with the IC₅₀ concentration. PUREG4-OCEI24, which is more hydrophobic and less cationic than PUREG4-OEI48, exhibits cytotoxic effects on cancer cells and inhibits wound healing after 24 hours, and its mechanism of action may be partially associated with cell necrosis. Based on our results, we conclude that both core-shell polycationic PURE dendrimers target the mitochondrial membrane, activating distinct cell death mechanisms.