科研之友
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摘要
Background and Aims Currently temozolomide (TMZ) as a potent agent is widely used to treat the glioblastoma multiforme (GBM), whereas recurrence due to intrinsic or acquired therapeutic resistance often occurs. Combination chemotherapy with TMZ may be a promising therapeutic strategy to improve treatment efficacy. Methods Aspirin, TMZ, and aspirin-/TMZ-coloaded poly (L-lactide-co-glycolide) (PLGA) microspheres were prepared by spray drying, and cytotoxicities of glioblastoma cells were measured. Results Aspirin microsphere treatment induced slight apoptosis and modestly inhibited proliferation of LN229 and U87 cells in vitro and in vivo through inhibition of beta-catenin transactivation. However, aspirin-/TMZ-coloaded microspheres presented synergistic antitumor efficacy compared with single TMZ-loaded microspheres. Aspirin/TMZ microspheres induced more apoptosis and repressed proliferation of LN229 and U87 cells. Corresponding to inhibition of beta-catenin signaling, beta-catenin/TCF4 transcriptional activity and STAT3 luciferase activity were strongly suppressed, and downstream targets expression was decreased. Furthermore, aspirin/TMZ microsphere intratumoral injection downregulated the expression of beta-catenin, TCF4, pAKT, pSTAT3, and PCNA and delayed tumor growth in nude mice harboring subcutaneous LN229 xenografts. Conclusions Aspirin sensitized TMZ chemotherapy efficacy through inhibition of beta-catenin transactivation; furthermore, the coloaded microspheres achieved a sustained release action to reduce the TMZ dosage, offering the potential for improved treatment of glioblastomas.
