Nanostructured lipid carrier co-delivering paclitaxel and doxorubicin restrains the proliferation and promotes apoptosis of glioma stem cells via regulating PI3K/Akt/mTOR signaling

The development of safe and efficient nanocomposites remains a huge challenge in targeted therapy of glioma. Nanostructured lipid carriers (NLCs), which facilitate specific site drug delivery, have been widely used in glioma treatment. Herein, we aimed to investigate the underlying mechanisms and therapeutic impact of paclitaxel (PTX) and doxorubicin (DOX) loaded NLC (PTX-DOX-NLC) on glioma stem cells (GSCs). To this end, we used a melt-emulsification technique to generate PTX loaded NLC (PTX-NLC), DOX loaded NLC (DOX-NLC), and NLC loaded with both drugs (PTX-DOX-NLC). We firstly confirmed the stability of PTX-DOX-NLC and their ability to gradually release PTX and DOX. Next, we evaluated the effects of PTX-DOX-NLC on apoptosis and proliferation of GSCs by flow cytometry and CellTiter-Glo assay. Besides, the expression of relevant mRNA and proteins was determined by RT-qPCR and Western blot analysis, respectively. Mechanism of action of PTX-DOX-NLC was determined though bioinformatic analysis based on RNA-seq data performed in GSCs derived from different NLC-treated groups. In addition, a mouse xenograft model of glioma was established to evaluate the anti-tumor effects of PTX-DOX-NLC in vivo. Results indicated thar PTX-DOX-NLC showed greater inhibitory effects on proliferation and promotive effects on apoptosis of GSCs compared with PTX-NLC, DOX-NLC, free PTX, and free DOX treatment. Mechanistic investigations evidenced that PTX-DOX-NLC inhibited tumor progression by suppressing the PI3K/AKT/mTOR signaling in vitro and in vivo. Taken together, PTX-DOX-NLC played an inhibitory role in GSC growth, highlighting a potential therapeutic option against glioma. (paper)