Crosslinked hydroxypropyl-β-cyclodextrin nanoparticles for improved efficacy of venetoclax against triple negative...

Bcl-2 protein plays an integral role in hijacking apoptosis and triggering chemoresistance in triple negative breast cancer (TNBC). The present study explored the therapeutic efficacy of Bcl-2 inhibitor i.e., venetoclax (VTX) loaded HP-β-CD NPs (VTX/HP-β-CD NPs) against TNBC. VTX/HP-β-CD NPs were prepared using nanoprecipitation method. The prepared nanoparticles had optimal size (∼217 ± 4.32 nm), narrow PDI (∼0.23 ± 0.01), higher drug loading (∼15.7 ± 1.94 %) and % entrapment efficiency (∼78.5 ± 1.09 %). Morphology assessment revealed a spherical shape. In-vitro release studies displayed sustained release for up to 72h. Moreover, VTX/HP-β-CD NPs exhibited higher cellular uptake, cytotoxicity, and apoptosis index than free drug. Furthermore, the IC₅₀ values for VTX/HP-β-CD NPs were significantly reduced in 4T1 (∼3.96-fold) and MDA-MB-231 (∼5.23-fold) cells. Additionally, VTX/HP-β-CD NPs showed remarkable potential to induce "mixed cell death" by reducing the glutathione (GSH) levels and increasing ROS in TNBC cells. The pharmacokinetic studies showed a marked increase in the AUC_0-∞ (∼2.12-fold), C_max (∼1.05-fold), and t_1/2 (∼1.66-fold). Also, anti-cancer efficacy studies in 4T1-based model revealed improved therapeutic efficacy of VTX when delivered via HP-β-CD NPs. Safety evaluation revealed no signs of toxicity. Overall, the prepared nanocarrier holds significant promise in enhancing the payload and efficacy of VTX.