Folic acid-conjugated chitosan/sodium hyaluronate-based hybrid nanocarriers as a dual-targeted delivery system for efficient breast cancer therapy

Breast cancer (BC) remains one of the most pressing health concerns today, affecting a significant number of women annually. Folate receptors (FRs) serve as unique targets that enhance the effectiveness of drug delivery while minimizing the side effects associated with chemotherapy. The current study aimed at developing, optimization and evaluation of a new hybrid core-shell polymeric nanoparticulate delivery system composed of folic acid (FA)-conjugated chitosan (CS), sodium hyaluronate (SH), and pluronic 123® (P123). The selection of components for the new nanocarrier system was strategically based on their complementary characteristics to allow efficient dual-targeted breast cancer (BC) treatment. FA was conjugated to CS, and their effective conjugation was ascertained through amide bond formation. Artocarpus heterophyllus (AH) extract was loaded, as a model bioactive agent, to assess the new nanocarrier. The optimized AH-loaded FA-CS/SH/P123 core-shell nanoparticles (AHNPs) possess desirable physicochemical properties, including particle size of 221 ± 11 nm and zeta potential of +32 ± 2.8 mV, indicating colloidal stability. The AHNPs also demonstrated a high entrapment efficiency (92 %) and loading capacity (31 %). In-vitro release tests achieved a controlled and sustained release profile at the cancer physiological pH. Besides, AHNPs exhibited a significantly lower IC₅₀ value (43.4 ± 3.3 μg/mL) compared to free AH (53.2 ± 3.4 μg/mL) and the plain nanoformulation (246.4 ± 7.7 μg/mL), indicating an improvement in the AH cytotoxicity against MCF-7 BC cells. The FA-conjugated AHNPs demonstrated higher cellular uptake than the bare NPs, demonstrating that the newly developed AHNPs can enhance the AH's anticancer efficacy by targeting FR-overexpressing breast tumors. In tumor-bearing mice, AHNPs have reduced tumor volume compared to free AH, confirming the augmented AH anticancer efficacy. In conclusion, the study findings suggest that the developed FA-conjugated-CS based NPs presents a promising delivery system for BC treatment.