Magnetic-guided targeted delivery of zerumbone/SPION co-loaded in nanostructured lipid carrier into breast cancer cells

Zerumbone (ZER), a potential anticancer agent for breast cancer treatment, has limited clinical applications due to its poor water solubility and targeting ability. The poor water solubility of ZER has been partly overcome by loading into nanostructured lipid carriers (ZER-NLC). However, the lack of targeting and selectivity is still a concern in clinical settings. To overcome these limitations, ZER-NLC was co-loaded with an active-targeting agent known as superparamagnetic iron oxide nanoparticles (SPION) that may direct ZER-NLC to the tumor site with an external magnetic field. This multi-modal therapeutic regime (ZER-SPION-NLC) was optimized using Box-Behnken design with good physicochemical properties, stability, and hemocompatibility. ZER-SPION-NLC was milky brownish in color with an average diameter of 140.32 ± 1.14 nm, polydispersity index of 0.18 ± 0.02, and zeta potential of −13.37 ± 0.61 mV. Transmission electron microscopy analysis confirmed the homogeneous, spherical, and uniform distribution of ZER-SPION-NLC. The release of ZER from the carrier followed zero-order kinetics and showed no significant differences in both acidic and physiological conditions, proving that the drug release was pH-independent. The ZER-SPION-NLC was cytotoxic against non-cancerous Vero. STAT1 cells, both MCF-7 and MDA-MB-231 breast cancer cell lines with half maximal inhibitory concentration values of 1.46 ± 0.33 μg/mL, 1.85 ± 0.15 μg/mL and 1.81 ± 0.16 μg/mL, respectively at 72 h of treatment. Interestingly, ZER-SPION-NLC showed a higher apoptotic effect towards MDA-MB-231 (29.63%) than MCF-7 cells (13.37%) at 48 h. This observation could be explained by the different half maximum uptake value (Km) and internalization mechanisms of ZER-SPION-NLC in these two cell lines. The uptake of ZER-SPION-NLC in MDA-MB-231 was via an active energy-dependent process with a faster uptake rate (Km value = 6 min) while the uptake in MCF-7 cell line is slower (Km value = 25 min) via caveolae-mediated endocytosis. Under a 0.5 T magnetic field, the magnetic properties of SPION were sufficient to direct ZER-SPION-NLC, resulting in increased uptake by 40.41% in MDA-MB-231 cells and 19.35% in MCF-7 than non-magnetic targeted cells. In conclusion, ZER-SPION-NLC could be a potential magnetic guiding multi-modal therapeutic system for breast cancer treatment. [Display omitted]