Development and evaluation of temozolomide loaded polymeric nanoparticles functionalized with a dendrimer and hyaluronic acid: An innovative nanotherapeutics for glioblastoma multiforme

Glioblastoma multiforme (GBM) remains therapeutically challenging due to the blood–brain barrier (BBB) and intrinsic tumor heterogeneity, significantly reducing drug efficacy. This study describes the engineering of multifunctional poly-DL-lactic-co-glycolic acid nanoparticles (PNP) loaded with temozolomide (TMZ) and surface-modified with polyamidoamine dendrimer (PD) and hyaluronic acid (HA), specifically designed for enhanced BBB penetration, receptor-mediated tumor targeting, and sustained drug release. PNP–TMZ@HA–PD were prepared via optimized nanoprecipitation using Vitamin E as a stabilizer, with PD and HA conjugation achieved through 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide chemistry. Characterization revealed optimal physicochemical parameters (particle size: ∼100 nm; polydispersity index: <0.15; and zeta potential: ≈ −20 mV), high drug encapsulation efficiency (91.66 %), and TMZ amorphization. Functionalized nanoparticles exhibited pH-sensitive release profiles (∼95.5 % at pH 5.5), robust stability in physiological environments, and minimal serum protein-induced aggregation. In vitro studies using U-87 MG cells confirmed significantly enhanced cellular uptake via HA-mediated CD44 receptor targeting, resulting in marked improvements in cytotoxicity (IC 50 = 4.98 μg/mL), reactive oxygen species (ROS) generation, and apoptotic induction compared to free TMZ. Thus, PNP–TMZ@HA–PD demonstrates significant therapeutic potential as a targeted nanotherapeutic platform for GBM, meriting further in vivo evaluation toward clinical translation.