Combination Therapy Using Carvedilol and 5-Fluorouracil Loaded Exosomes As a Novel Synergistic Strategy Against Breast Cancer

Despite advances in cancer treatment, chemoresistance and toxicity remain significant challenges in breast cancer therapy. This study investigated the synergistic effects of carvedilol (CAR), a non-selective beta and alpha1 blocker with emerging anticancer properties, combined with 5-fluorouracil (5-FU), a standard chemotherapeutic agent limited by resistance development and systemic toxicity. We explored this combination as a novel drug repurposing strategy to overcome resistance while enhancing therapeutic efficacy in MCF-7 and MDA-MB231 breast cancer cell lines. The Chou-Talalay method revealed significant synergistic interactions between these drugs, with an optimal 5-FU:CAR ratio of 4:1 (CF). An exosome-mediated co-delivery system (CF-Exo) was developed for these drugs to enhance drug delivery, followed by characterization and assessment of their efficacy in vitro. Drug loading was performed through sonication, achieving about 30 % efficiency. Drug release studies demonstrated higher release rates in acidic pH (65 % for 5-FU, 36 % for CAR) compared to pH 7.4 (59 % for 5FU, 11 % for CAR). CF-Exo demonstrated enhanced cellular uptake compared to free drug combinations. The CF drug combination increased apoptosis compared to the same concentration of 5-FU or CAR in both cell lines. CFExo also maintained CF's apoptotic activity. Following studies revealed that the combination treatment primarily induced apoptosis, with increased reactive oxygen species (ROS) generation and decreased mitochondrial membrane potential (MMP). These findings suggest that the synergistic interaction between CAR and 5-FU, coupled with the exosome-mediated delivery system, may provide a promising approach for enhancing breast cancer treatment efficacy and potentially overcoming drug resistance.