Co-delivery of TRAIL gene enhances the anti-glioblastoma effect of paclitaxel in vitro and in vivo

Co-delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel (PTX) is an attractive strategy to enhance their anti-tumor efficacy. As the most aggressive brain tumor, glioblastoma is sensitive to TRAIL and PTX. However, their therapeutic efficacy for intracranial glioblastoma is significantly impaired by blood–brain barrier (BBB) and blood–tumor barrier (BTB). Previously, we have prepared c(RGDyK)–poly(ethylene glycol)–polyethyleneimine (RGD–PEG–PEI) as a non-viral gene carrier for glioblastoma targeted therapy by employing a cyclic RGD peptide (c(RGDyK), cyclic arginine–glycine–aspartic acid–d-tyrosine–lysine), which binds to integrin αvβ3 over-expressed neovasculature and U87 glioblastoma cells with high affinities. In the present work, it was found that low concentration of paclitaxel (10 nM) significantly enhanced the gene transfection of RGD–PEG–PEI/pDNA nanoparticle, which, in turn, dramatically elevated the anti-glioblastoma effect of paclitaxel in vitro. The gene transfection was also elevated in vivo. Co-delivery of brain-targeted CDX–PEG–PLA–PTX micelle dramatically enhanced gene transfection efficiency in the intracranial brain tumor. Due to the change of BBB integrity and the formation of BTB, we subsequently investigated the anti-glioblastoma effects of RGD–PEG–PEI/pORF-hTRAIL nanoparticle combined with CDX–PEG–PLA–PTX micelle (paclitaxel loaded CDX–poly(ethylene glycol)–block-poly(lactic acid) micelle). While at the same dosages, the median survival of the intracranial glioblastoma-bearing model mice treated with co-delivery (33.5 days) is significantly longer than those of solely treated mice with CDX–PEG–PLA–PTX (25.5 days), RGD–PEG–PEI/pORF-hTRAIL (24.5 days) or physiological saline (21.5 days). Herein, we verify the high potency of co-delivery of TRAIL gene and paclitaxel in the intervention of intracranial glioblastoma by employing tumor-targeted gene carrier RGD–PEG–PEI and brain-targeted micelle CDX–PEG–PLA, respectively.

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