摘要
Temozolomide (TMZ) is a clinically approved drug for glioblastoma (GBM) therapy. However, as a result of methylguanine-DNA-methyltransferase (MGMT), which is able to repair damaged DNA-damage repairing, TMZ usually yields unsatisfactory therapeutic effects. Small interfering RNA (siRNA) is a potential alteration tool for sensitivity of TMZ by targeting DNA repair enzymes. However, a suitable TMZ and siRNA codelivery system that can effectively and actively co-deliver siRNA/TMZ into the brain tumor is lacking. In this study, we constructed an angiopep-2 decorated polymersomal delivery system to co-deliver TMZ/siRNA for synergistic GBM therapy. This targeted polymersomal nanomedicine not only enhanced the circulation time of siRNA/TMZ in blood but also improved their blood-brain barrier (BBB) crossing and GBM targeting ability. Moreover, when we co-administered siRNAs specific to retinoblastoma binding protein 4 (RBBP4) together with TMZ in GBM cells, these RBBP4- specific siRNA (siRBBP4) modulated the sensitivity of TMZ by regulating MGMT, and thus showed a powerful synergistic anti-tumor effect. We demonstrated that angiopep-2 decorated polymersomal siRBBP4/TMZ co-loaded nanomedicines are capable of inhibiting tumor growth and significantly improved life expectancy of orthotropic GBM bearing mice. Overall, our study suggests that such a polymersomal TMZ/siRNA codelivery system provides a robust and potent nanoplatform for targeted GBM chemo-RNAi therapy.
基金
This research was funded by China’s National Key Technologies R&D Programs(2018YFA0209800)
National Natural Science Founda tion of China(NSFC 52073079,31800841,32071388,and U1804139)
Key Research Program in Colleges and Universities of Henan Province(19zx006)
Program of Technology Innovation Team in Colleges and Universities of Henan Province(21IRTSTHN028)
NHMRC Investi-gator Grant.
