In the last decades, numerous dendrimers with a variety of potential biomedical applications have been developed and investigated. The aim of the present study was to evaluate the molecular mechanisms of interaction between two dendrimers with proven antibacterial activity (4-N,N-dimethylamino-1,8-naphthalimide (Dab) and 3-bromo-Dab (Dab-Br)) and POPC (1-palmitoyl-2-oleoylphosphatidylcholine) model membranes (monolayers and liposomes). The pressure-area isotherms and the compressional modulus of the monolayers revealed that Dab is likely to penetrate the hydrophobic region of POPC, whereas Dab-Br inserts mainly into the lipid headgroup area. This assumption was confirmed by FTIR-ATR of POPC liposomes containing Dab and Dab-Br dendrimers. In addition, Dab induced a higher lipid order in POPC large unilamellar vesicles (LUVs) compared to Dab-Br. Moreover, both dendrimers changed the negative zeta potential of POPC vesicles to positive values, with slightly higher effect of Dab-Br, indicating electrostatic interactions between the lipid headgroups and dendrimers. Furthermore, Dab was able to reduce the average POPC LUVs’ size, unlike Dab-Br. The visualization of giant unilamellar vesicles revealed that the increasing dendrimer concentration induced model membrane shrinking and complete disintegration, which was more prominent for Dab. Based on the experimental results, new fundamental knowledge about the destabilizing effect of dendrimers on model lipid membranes will be acquired with a focus on their application in pharmacology and clinical practice.

Dendrimers, 4-dimethylamino-1,8-naphthalimide (DAB) and its halogenated analog 3-bromo-4-dimethylamino-1,8-naphthalimide (DAB-Br), were evaluated on eukaryotic cells, human HFF-1 fibroblast cells, and five fungal species. Although both dendrimers have demonstrated antibacterial and antiviral potential, thus far, their effects on eukaryotic cells, particularly human and fungal cells, have not been investigated. For this purpose, their cytotoxicity, mechanisms of cellular entry, and antifungal activity were studied. Dynamic light scattering measurements revealed that both dendrimers exhibited positive surface charges (+28 to +35 mV), good colloidal stability, and nanoscale dimensions (117–234 nm), facilitating interactions with target cells. The MTT assay showed that DAB was more cytotoxic toward HFF-1 cells (IC₅₀ = 27 µg/mL) compared to DAB-Br (IC₅₀ = 68 µg/mL). In contrast, the resazurin-based antifungal assay demonstrated that DAB-Br had superior antifungal activity, achieving a lower minimum inhibitory concentration (0.148 µg/µL), compared to DAB (0.295 µg/µL). A trypan blue exclusion test revealed that both dendrimers entered cells through membrane permeabilization, either temporarily or permanently, depending on the concentration and exposure time. At concentrations above 30 µg/mL, irreversible permeabilization was observed within two hours of treatment, accompanied by a decrease in membrane lipid order, indicating altered membrane integrity and permeability. Conversely, at lower concentrations (7.5–15 µg/mL), dendrimers induced only temporary membrane permeabilization, with membranes remaining intact, suggesting a reversible interaction with the lipid bilayer. Conducting thorough and systematic research to fully explore their biological activities could provide valuable insight for future applications.