Molecular and Antiangiogenic Effects of Paclitaxel-Loaded Nanoparticles: Influence of the Nanocarrier Type

Nanostructured lipid carriers (NLCs) and lipid-polymeric hybrid nanoparticles (H-NPs) were developed for the local administration of paclitaxel (PTX) and breast cancer therapy. Here, we investigated how nanoparticle type and composition influence the molecular effects and in vivo antiangiogenic activity of PTX. Elevated BAX expression and PARP-1 cleavage in MCF-7 and MDA-MB-231 breast cancer cells treated with nanoencapsulated PTX indicate that apoptosis is the primary mechanism of cell death, regardless of the nanocarrier type. However, distinct molecular effects were observed for other markers. Both unloaded nanocarriers increased α-tubulin acetylation in MCF-7 cells, indicating an intrinsic ability of the carriers to modulate cytoskeletal organization. Upon PTX loading, these effects became carrier-dependent: NLC-PTX induced higher α-tubulin acetylation than H-NP-PTX compared to the PTX solution. Moreover, in MCF-7 cells, NLC-PTX, but not H-NP-PTX, markedly enhanced drug-induced DNA damage, increasing γH2AX expression by 13.4-fold compared to PTX as a solution. These findings suggest that the nanocarriers not only act as delivery systems but may also confer additional biological effects that may contribute to PTX cytotoxicity. In the chicken chorioallantoic membrane model, nanoencapsulation reduced PTX-induced irritation from moderately irritant (irritation score 6) to nonirritant while preserving its antiangiogenic activity, achieving a 6.1-7.8-fold inhibition of vessel growth at subcytotoxic doses. Collectively, these results highlight nanoencapsulation as a promising strategy to potentiate PTX activity while improving safety for local breast cancer therapy. The distinct molecular responses of lipid and hybrid systems demonstrate that nanocarrier composition and structure modulate biological outcomes, underscoring the importance of rational nanocarrier design to overcome current therapeutic challenges.