Design and characterization of phloretin-loaded PEG-lipid hybrid micelles for enhanced breast cancer therapy

Breast cancer remains a leading cause of mortality among women worldwide, emphasizing the urgent need for innovative therapeutic strategies. Phloretin, a natural dihydrochalcone flavonoid with potent anticancer activity, is limited by poor aqueous solubility and bioavailability. To overcome these challenges, phloretin was encapsulated in PEG-lipid hybrid micelles (PLHMs) formulated from PEG 4000, soy lecithin, and cholesterol. Optimization via a central composite design yielded the optimized formulation (F14), which exhibited a vesicle size of 190.6 ± 5.3 nm, a polydispersity index of 0.201 ± 0.01, and a zeta potential of - 28.5 ± 1.9 mV, indicating nanoscale uniformity and excellent colloidal stability. The formulation achieved an entrapment efficiency of 95.0 ± 1.6%, significantly higher than that of free phloretin. In vitro release studies demonstrated a biphasic release profile characterized by an initial burst followed by sustained release, with 67.2 ± 1.4% of the drug released over 24 h. Notably, phloretin solubility improved 2.2-fold compared to the pure compound. Cytotoxicity evaluation using the MTT assay on MCF-7 breast cancer cells revealed an IC₅₀ of 38 ± 2.8 μM for PLHMs, compared to 20 ± 1.5 μM for 5-fluorouracil. These findings highlight the promise of PLHMs as effective nanocarriers for phloretin, offering enhanced drug encapsulation, controlled release, and improved anticancer efficacy for breast cancer treatment.