Chitosan nanoparticles loaded with metformin and digoxin synergistically inhibit MCF-7 breast cancer cells through suppression of NOTCH-1 and HIF-1α gene expression

• Published in: International journal of biological macromolecules 2024-12, Vol.287, p.138418, Article 138418
• Main Authors: Dadashi, Hamed, Mashinchian, Milad, Karimian-Shaddel, Alireza, Mohabbat, Aria, Vandghanooni, Somayeh, Eskandani, Morteza, Jahanban-Esfahlan, Rana
• Format: Article
• Language: English
• Subjects: Chitosan nanoparticles; Combination therapy; Digoxin; Engineering; HIF-1a; Metformin; NOTCH-1
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.138418

This study investigated the potential anticancer efficacy of co-treating the MCF-7 breast cancer cell line with chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and digoxin (Dig). The Cs NPs had a size range of 90.6–148.7 nm and a zeta potential of +11.7 to +11.9 mV, indicating a positive surface charge. Notably, the Cs NPs demonstrated high encapsulation efficiencies, with values of 90.97 ± 5.14 % for Met and 92.12 ± 3.81 % for Dig, indicating effective loading of both drugs. The results revealed that the co-delivery of Met and Dig via Cs NPs significantly enhanced the anticancer efficacy, outperforming the treatment with individual free drugs or their combination, thereby demonstrating the potential benefits of nanoparticle-mediated co-administration. The drugs-loaded Cs NPs induced a marked increase in apoptosis in MCF-7 cells, with a cell death rate of 67.56 %, and significantly reduced mammosphere size by 48.08 %, thereby demonstrating a superior therapeutic efficacy compared to treatment with individual free drugs or their combination. Notably, the drug-loaded Cs NPs exhibited potent anti-migratory and anti-angiogenic effects, significantly inhibiting cell migration and new blood vessel formation, which may contribute to overcoming the inherent resistance of tumors to conventional therapies. Mechanistically, the co-treatment with drugs-loaded Cs NPs was found to downregulate the expression of NOTCH-1 and HIF-1α, two key transcription factors involved in tumor cell survival and adaptation, suggesting that their inhibition is a crucial component of the therapeutic efficacy of this treatment strategy. Collectively, the findings of this study suggest that the co-delivery of Met and Dig via chitosan Cs NPs represents a promising therapeutic strategy for breast cancer, as it effectively targets key pathways involved in tumor growth and progression, and underscores the potential of Cs NPs as a versatile platform for cancer therapy. [Display omitted]