Exploring the Co-delivery of Sorafenib and Venetoclax to Induce Ferroptosis and Apoptosis Mediated Cancer Cell Death using Surface Modified PLGA Nanoparticles.

Chemotherapy resistance continues to represent a profound impediment in oncologic therapy, and the co-delivery of chemotherapeutic agents with distinct mechanisms of action offers an effective approach. In the present investigation, we developed Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Sorafenib (SOR), a ferroptosis inducer, and Venetoclax (VTX), an apoptosis inducer for combined cell death. These PLGA(SOR + VTX) NPs were formulated via nanoprecipitation followed by successive coating with polydopamine (PDA) and bovine serum albumin (BSA). PDA was utilized to facilitate BSA linkage while BSA enabled targeting of albondin and secreted protein acidic and rich in cysteine (SPARC) receptors. BSA-PDA-PLGA(SOR + VTX) NPs revealed a spherical morphology with a size of 183.6 ± 6.20 nm, a PDI of 0.108 ± 0.02, and a Z-potential of -23.3 ± 1.03 mV with SOR and VTX ratiometrically (1:1) loaded into the nanoparticles. The nanoparticles exhibited sustained release behaviour and were assessed to be hemocompatible. The cell uptake studies reflected better cytoplasmic internalization, and the formulation resulted in a reduction in the IC50 value by 2.74, 3.40, and 2.90-fold compared to the physical combination of SOR + VTX in MDA-MB-231, A549, and HeLa cell lines, respectively. The apoptosis index of the formulation was 1.42, 1.40 and 1.40-fold higher than that of SOR + VTX in MDA-MB-231, A549 and HeLa, respectively. Moreover, BSA-PDA-PLGA(SOR + VTX) NPs induced a greater generation of reactive oxygen species and mitochondrial membrane potential depolarization. They also demonstrated escalated ferroptosis by depleting glutathione and elevating malondialdehyde levels across all cell lines. Thus, co-delivery of SOR and VTX via BSA-PDA-PLGA NP exhibited synergistic activity in targeting different tumor cells.