Magnetic hyperthermia-triggered multi-functional thermo-responsive lipid nanoparticles for enhanced paclitaxel release and cytotoxicity

Abstract

The inadequate safety and efficacy of chemotherapy have led cancer medicine to focus on localizing drug delivery to the target. Thermoresponsive nanocarriers (liposomes and polymeric networks) exploit local hyperthermia to trigger targeted payload release; however, their low stability and unpredictable fate in vivo have led to failure in clinical studies. To overcome these challenges, we reported first-of-its-kind thermoresponsive lipid nanoparticles (TLNs) that undergo solid–liquid phase transition under hyperthermia to release the payload. This study enabled TLNs with on-demand drug delivery functionality to breast cancer cells by incorporating magnetically activated iron oxide nanoparticles (γ-Fe₂O₃) into a lauric and oleic acid-based phase-changing lipid-matrix to synthesize paclitaxel (PTX)- and γ-Fe₂O₃-loaded TLNs (P-γ-TLN). Critical independent variables were selected and then optimized using a central composite design to obtain the optimized formulation, P-γ-TLN 12, with a size of ∼183 nm, polydispersity of 0.50, zeta potential of −22 mV, and encapsulation efficiencies of 85% for PTX and 60.49% for γ-Fe₂O₃. Thermoresponsive delivery was confirmed, with TLNs remaining relatively stable at 37 °C for 72 h, releasing only 34.26% of the drug, whereas exposure to 45 °C resulted in more than a two-fold increase, releasing 79.35% over the same period. Under an external alternating magnetic field, γ-Fe₂O₃ generated hyperthermia and induced a phase transition in P-γ-TLN, leading to abrupt drug release. Both γ-Fe₂O₃ and TLNs exhibited high biocompatibility, but TLN encapsulation significantly improved uptake in MCF-7 breast cancer cells. Under AMF, P-γ-TLN showed enhanced PTX release, resulting in more potent cytotoxicity against MCF-7 cells. The combination of high payload capacity, stimuli-responsive release, thermotherapy, and enhanced chemotherapeutic response highlights the substantial potential for TLNs in cancer therapy.