Synergistic anticancer therapy via ferroptosis using modified bovine serum albumin nanoparticles loaded with sorafenib and simvastatin.

Ferroptosis is a non-apoptotic cell death pathway characterized by the accumulation of lipid-peroxy radicals within the affected cells. Here, we investigate the synergistic capacity of sorafenib (SOR) and simvastatin (SIM) to trigger ferroptosis for cancer therapy. For precise in-vivo delivery, SOR + SIM was ratiometrically loaded in bovine serum albumin nanoparticles (BSA-NPs) modified with 4-carboxy phenylboronic acid (CPBA). The developed CPBA-BSA(SOR + SIM)-NPs revealed size of 175.2 ± 12.8 nm, with PDI of 0.22 ± 0.03 and Z-potential of -29.6 ± 4.8 mV. Significantly, CPBA-BSA(SOR + SIM)-NPs exhibited > 2 and > 5-fold reduction in IC50 values compared to individual SOR and SIM treatments respectively, in all tested cell lines. Moreover, CPBA-BSA(SOR + SIM)-NPs treated cells exhibited decrease in glutathione levels, increase in malonaldehyde levels and depolarization of mitochondrial membrane potential (JC-1 assay). Pharmacokinetic analysis revealed enhanced AUC0-∞ and MRT levels for SOR and SIM when administered as CPBA-BSA(SOR + SIM)-NPs compared to free drugs. Crucially, in in-vivo experiments, CPBA-BSA(SOR + SIM)-NPs led to a significant reduction in tumor volume compared to various control groups. Histological and biomarker analyses underscore their biocompatibility for clinical applications. In conclusion, this study highlights the potential of CPBA-BSA(SOR + SIM)-NPs as a promising strategy for inducing ferroptosis in cancer cells, concurrently improving drug delivery and therapeutic efficacy. This approach opens new avenues in cancer treatment.

Exploring Sorafenib and Simvastatin Combination for Ferroptosis-Induced Cancer Treatment: Cytotoxicity Screening, In Vivo Efficacy, and Safety Assessment.

Ferroptosis, a pathway dependent on oxygen and iron catalysts, holds promise as a therapeutic approach for cancer treatment due to its manageable regulation, direct control, and immunogenic properties. The sensitivity of cancer cells to ferroptosis induction varies based on their metabolic, genetic, and signalling pathways, prompting the use of combination therapy. In this study, we conducted a screening of drug combinations, including sorafenib (SOR) with simvastatin (SIM), phenethyl isothiocyanate, and trigonelline, in MDA-MB-231, A549, and HeLa cells to assess their cytotoxicity. The SOR-SIM combination exhibited a synergistic effect in MDA-MB-231, A549, and HeLa cells, with calculated CI values of ~ 0.66, 0.53, and 0.59, respectively. Furthermore, co-treatment with ferrostatin-1 resulted in a concentration-dependent increase in the IC50 values. Additionally, SOR + SIM demonstrated a significant reduction in GSH levels, an increase in MDA levels, and mitochondrial membrane depolarization across all three cell lines, indicating their ferroptosis inducing potential. In-vivo studies showed a significant reduction in tumor volume by 3.53-, 2.55-, and 1.47-fold compared to control, SIM, and SOR, respectively. Toxicity assessments revealed insignificant changes in biomarker levels and no observable deformations in isolated organs, except for erythrocyte shrinkage and membrane scrambling effects caused by the SOR + SIM combination. Overall, our findings highlight the potential of the SOR + SIM combination as an effective strategy for cancer treatment, emphasizing the importance of further research in targeted drug delivery systems to ensure its safety.