Transferrin-Conjugated PLGA Nanoparticles for Co-Delivery of Temozolomide and Bortezomib to Glioblastoma Cells

Glioblastoma (GBM)represents almost half of primarybrain tumors,and its standard treatment with the alkylating agent temozolomide(TMZ) is not curative. Treatment failure is partially related to intrinsicresistance mechanisms mediated by the O6-methylguanine-DNA methyltransferase(MGMT) protein, frequently overexpressed in GBM patients. Clinicaltrials have shown that the anticancer agent bortezomib (BTZ) can increaseTMZ's therapeutic efficacy in GBM patients by downregulatingMGMT expression. However, the clinical application of this therapeuticstrategy has been stalled due to the high toxicity of the combinedtherapy. The co-delivery of TMZ and BTZ through nanoparticles (NPs)of poly(lactic-co-glycolic acid) (PLGA) is proposedin this work, aiming to explore their synergistic effect while decreasingthe drug's toxicity. The developed NPs were optimized by centralcomposite design (CCD), then further conjugated with transferrin(Tf) to enhance their GBM targeting ability by targeting the blood-brainbarrier (BBB) and the cancer cells. The obtained NPs exhibited suitableGBM cell delivery features (sizes lower than 200 nm, low polydispersity,and negative surface charge) and a controlled and sustained releasefor 20 days. The uptake and antiproliferative effect of the developedNPs were evaluated in in vitro human GBM models.The obtained results disclosed that the NPs are rapidly taken up bythe GBM cells, promoting synergistic drug effects in inhibiting tumorcell survival and proliferation. This cytotoxicity was associatedwith significant cellular morphological changes. Additionally, thebiocompatibility of unloaded NPs was evaluated in healthy brain cells,demonstrating the safety of the nanocarrier. These findings provethat co-delivery of BTZ and TMZ in Tf-conjugated PLGA NPs is a promisingapproach to treat GBM, overcoming the limitations of current therapeuticstrategies, such as drug resistance and increased side effects.