Monocyte-hitchhiking system for the targeted delivery of paclitaxel-loaded PLGA nanoparticles to glioblastoma in mice

Cell-based therapy for the treatment of glioblastoma (GBM) has gained a lot of attention as a minimally invasive drug delivery strategy because of its potential to overcome the blood-brain barrier (BBB) impediment and target the tumor microenvironment. Here, we evaluate the targeting efficacy of a monocyte-mediated nanoparticle (NP) drug delivery system for the treatment of GBM. First, the efficacy of various drugs, including paclitaxel (PTX), doxorubicin (DOX), temozolomide (TMZ) and Gboxin is tested in GBM, endothelial and monocytic cell lines in order to evaluate the ideal drug to be loaded in our monocyte-nanoparticle delivery system. PTX has shown the most optimal cancer selective potency against mouse and human GBM cells, and thus, has been chosen to be loaded into the NP delivery system. Therefore, PTX loaded biotinylated polyethylene glycol- poly (lactic-co-glycolic acid) (biotin-PEG-PLGA) NPs are synthesized and conjugated to monocytes via biotin-streptavidin interactions. NP conjugation efficiency and viability of monocytes is investigated after the conjugation of WEHI-3 or bone-marrow derived monocytes (BMDMs) with different cell:NP ratios. Our data show that BMDMs have higher viability, 48 h after NP conjugation, and better transmigration abilities across an in vitro BBB model and towards a monocyte chemoattractant protein-1 (MCP-1) gradient. Importantly, conjugation of NPs to BMDMs with 1:5000 cell:NP ratio does not affect the transmigration ability of the monocytes and NPs show improved brain targeting when are conjugated to BMDMs compared to free injected NPs, in an orthotopic GBM mouse model. Overall, our data provides evidence for successful targeting of GBM tumors in mice with our BMDM-PLGA-PTX delivery system, holding promise as a future therapeutic strategy.