Repurposing felodipine via hyaluronic acid-coated cetylosomes (HCCs) for parenteral active targeting of cancer: Box-Behnken statistical optimization, in vitro characterization, and in vivo studies.

Felodipine (FEL), an antihypertensive drug, is being repurposed as an anticancer drug. It has low oral bioavailability due to its extensive metabolism in the liver and poor water solubility. This study aimed to develop hyaluronic acid-coated cetylosomes (HCCs) for parenteral delivery of FEL to boost its solubility and anticancer efficacy. FEL-HCCs were prepared by the thin-film hydration technique based on Box-Behnken design. Amounts of cetyl alcohol, Brij 97, and hyaluronic acid were the independent factors. The optimized HCC (OHCC) formula which showed the highest desirability value (0.626), was composed of 100 mg Brij 97, 32.44 mg CA, and 10 mg HA. It showed the minimum vesicle size (156.72 nm) and polydispersity index (0.134), and the maximum entrapment efficiency% (72.04%) and zeta potential (-30.58 mV). After lyophilization and sterilization of the OHCC formula, it showed a 2.01-fold enhancement in FEL release compared to the market tablet, with no significant difference in release before and after lyophilization or sterilization. The sterilized OHCC was stable for six months. The OHCC showed an enhanced cytotoxicity against MCF-7 cells with 6.61-fold compared to pure FEL powder. Additionally, the OHCC potentiated the antiproliferative effect of doxorubicin, as evidenced by a raised Bax/Bcl-2 ratio and caspase 9 content, and suppressed VEGF levels. In vivo, the OHCC markedly reduced tumor growth, particularly in combination with doxorubicin. The histopathological investigation supported the apoptotic and necrotic death of cancer cells. These findings suggest that HCCs represent a promising nanocarrier system for the targeted parenteral delivery of FEL in cancer therapy.