Thermosensitive PluronicF127 Micelles for PiperlongumineDelivery: Selective ROS Amplification to Potentiate Cisplatin Efficacyin 3D Lung Cancer Spheroids

Abstract

Lung cancer remains a primary cause of cancer-related mortality worldwide, and cisplatin-based chemotherapy is often limited by its nonselective toxicity toward normal tissues and limited single-agent efficacy. To overcome these challenges, we developed a thermosensitive nanocarrier system utilizing Pluronic F127 (PF-127) to encapsulate Piperlongumine (PL)-a cancer-selective pro-oxidant reported to enhance cellular apoptotic responses to cisplatin treatment through ROS regulation and redox modulation. The PF-127 system leverages temperature-dependent self-assembly to form uniform spherical micelles with diameters below 100 nm at physiological temperature (37 degrees C), achieving a high drug loading efficiency (similar to 90%). Dynamic light scattering and transmission electron microscopy confirmed the formation of well-defined micelles and improved aqueous dispersibility of the hydrophobic PL. In vitro assays using A549 cells demonstrated that PL-loaded micelles significantly amplified intracellular ROS generation, promoting oxidative stress-associated apoptotic responses. This multidrug strategy markedly enhanced cisplatin-induced cytotoxicity in A549 cells. Crucially, in a 3D multicellular spheroid model, the treatment exhibited high cytotoxicity toward lung cancer spheroids (A549) while sparing normal lung fibroblast spheroids (MRC-5), consistent with the differential redox-handling capacities between malignant and healthy cells. These findings highlight the potential of ROS-amplified micellar delivery as a selective strategy to enhance cisplatin efficacy in lung cancer.