Hyaluronic acid–functionalized synergistic nanostructured lipid carriers for sustained release and enhanced bioavailability

Breast cancer remains one of the most prevalent malignancies among women and is the leading cause of morbidity and mortality. This study was designed to develop and statistically optimized co-loaded tamoxifen (TMX) and letrozole (LTZ) nanostructured lipid carrier coated with hyaluronic acid (HA-TMX-LTZ-NLCs) for synergistic activity towards breast cancer. Melt emulsification-ultra sonication method was used for the preparation of TMX-LTZ-NLCs, followed by their statistical optimization via Design-Expert. TMX-LTZ-NLCs were subsequently coated with HA for improved biopharmaceutical performance. The coating was confirmed using Fourier Transfrom Infrared Spectroscopy (FTIR) analysis. The optimized HA-TMX-LTZ-NLCs were characterized for particle properties, polymorphic form, thermal behavior and morphology using Dynamic Light Scattering (DLS), Powder Xray Diffractometry (PXRD), Differential Scanning Calorimetry (DSC) and Transmission Electron Microscopy (TEM), respectively. In vitro release analysis of HA-TMX-LTZ-NLCs was performed and in vitro antitumor potential was investigated in MCF-7 cells. Moreover, its synergistic activity was evaluated through CompuSyn software. Pharmacokinetic (PK) profile of HA-TMX-LTZ-NLCs was investigated after intravenous administration in rats. The optimized HA-TMX-LTZ-NLCs demonstrated a mean PS of 197.2 ± 5.9 nm, polydispersity index 0.192 ± 0.004 and zeta potential of -15.1 ± 0.60 mV. TEM, PXRD and DSC analysis respectively confirmed the spherical morphology and amorphous nature of the HA-TMX-LTZ-NLCs. Moreover, it demonstrated a sustained drug release and significantly higher antiproliferative effect. The HA-TMX-LTZ-NLCs exhibited a 2.4 ~ and 4.1 ~ fold reduced with IC 50 values when compared with HA-TMX-NLCs and HA-LTZ-NLCs, respectively. Furthermore, a strong synergistic effect was evident from the CompuSyn analysis. Additionally, PK study exhibited a 3.96 ~ and 3.65 ~ fold increased systematic exposure of TMX and LTZ, respectively. The sustained release, enhanced in vitro antitumor efficacy and improved bioavailability of HA-TMX-LTZ-NLCs suggests its therapeutic potential in breast cancer therapy.