Ternary Lipids-based Novel Thermoresponsive Lipid Nanoparticles for Targeting Doxorubicin to Breast Cancer Cells

Conventional thermoresponsive liposomes have failed to meet cancer targeting potential due to poor safety profile, unpredictable fate, and low therapeutic response in clinical studies. Recently, we reported phase-change nanostructured lipid carriers, termed thermoresponsive lipid nanoparticles (TLNs), for targeting cancer cells under hyperthermia. Herein, we have prepared ternary eutectic mixtures of myristic, stearic, and palmitic acid at a ratio of 2.5:1:1.5 yielded a melting point or solid-liquid phase transition temperature of 41°C. Doxorubicin (DOX)-loaded TLNs were fabricated and optimized using Box-Behnken Design Expert® software and exhibited desirable particle size (191.7±2.88 nm), polydispersity index (0.213±0.025), zeta-potential (-21.2±2.29 mV), spherical shape, high entrapment efficiency (92.24±1.05), and desirable physicochemical stability. In-vitro drug release studies showed hyperthermia-aided abrupt DOX release within 2 hours at 41°C and 43°C while sustained drug release pattern for 12 hours at 37°C. In-vitro cytotoxicity studies of TLN also exhibited the highest breast cancer (MCF-7) cells killing at hyperthermia (41°C), more than 3-fold compared to 37°C and free DOX solution. A 23-fold higher cell uptake in breast cancer cells further confirmed that ternary eutectic mixture-based DOX-loaded TLNs are an excellent candidate for breast cancer targeting and may be preferred over other nano-carriers due to the feasible preparation and superior stability.