Exploratory Study on Nanoparticle Co-Delivery of Temozolomide and Ligustilide for Enhanced Brain Tumor Therapy.

Temozolomide (TMZ) is the first-line therapy for glioblastoma (GBM), but its clinical efficacy is limited by its short half-life, poor brain targeting, adverse side effects, and the development of drug resistance. Ligustilide (LIG) has been shown to enhance blood-brain barrier permeability and reduce P-glycoprotein activity, thereby potentiating the synergistic effect of TMZ against GBM. The dual-drug-loaded nanoparticles encapsulating both TMZ and LIG (TMZ/LIG-NPs) were prepared using Poly (d,l-lactic-co-glycolide)-monomethoxy poly (ethylene glycol) (PLGA-mPEG). The physicochemical properties of the NPs, including particle size and zeta potential, were characterized. Cellular uptake of NPs was evaluated using flow cytometry and fluorescence staining. The pharmacokinetic profile and cytotoxicity of TMZ/LIG-NPs were compared to those of free TMZ and a mixture of TMZ and LIG in rat and glioma cells, respectively. The mean particle size of TMZ/LIG-NPs was 117.6 ± 0.7 nm, with a zeta potential of -26.5 ± 0.4 mV. Cellular uptake of NPs was significantly higher than that of free drug in U251 cells. Encapsulation of TMZ in NPs significantly increased its half-life by 1.62-fold compared to free TMZ and significantly improved its pharmacokinetic profile. Moreover, the storage stability of the TMZ/LIG-NPs solution was extended to one month. The toxicity of TMZ/LIG-NPs to glioma cells C6 and U251 was markedly enhanced compared to the mixture of TMZ and LIG. The development of TMZ/LIG-NPs using PLGA-mPEG effectively enhanced the stability and efficacy of both TMZ and LIG. This dual drug-loaded nanoparticle system represents a promising strategy for glioblastoma therapy.