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The aim of this study was to improve the therapeutic index of chemotherapeutic drugs on glioblastoma cells through an improved co-drug delivery system. Methotrexate (MTX) and paclitaxel (PTX) were co-loaded into poly (lactic- co -glycolic acid) nanoparticles (PLGA NPs) coated with polyvinyl alcohol (PVA) and Poloxamer188 (P188). The mean size of the NPs was about 212 nm, with a zeta potential of about −15.7 mV. Encapsulation efficiency (EE%) and drug loading (DL%) were determined to be 72% and 4% for MTX and 85% and 4.9% for PTX, respectively. The prepared NPs were characterized by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Moreover, an in vitro sustained release profile was observed for both drug loaded PLGA NPs. Glioblastoma cellular uptake of the NPs was confirmed by fluorescence microscopy and cell survival rate was investigated through the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method after 48 h of incubation showing IC 50 values of 24.5 μg·mL−1 for PTX and 9.5 μg·mL−1 for MTX for the MTX/PTX co-loaded PLGA nanoparticles coated with PVA/P188 (Co-2 NPs). Apoptosis and necrosis were also studied via flow cytometry, the lactate dehydrogenase (LDH) assay and the amount of anti-apoptotic protein (Bcl-2) expression. Blood compatibility of the co-delivery of PTX and MTX loaded PLGA NPs was investigated using a hemolysis method as well. The co-delivery of PTX and MTX loaded PLGA NPs is promising for the treatment of glioblastoma compared to their respective free drug formulations and, thus, should be further investigated. [ABSTRACT FROM AUTHOR]