Abstract
Systemic administration of therapeutic siRNA/microRNA for targeted treatment of glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP), named FA-pRNA-3WJ, based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA/microRNA for tumor cell killing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. FA-3WJ-LNA-miR21 specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. This RNA nanotechnology was employed even to regulate the anchoring of nanoparticles on the surface of extracellular vesicles (EVs) for specific cancer targeting and intracellular trafficking. Taking advantage of the RNA aptamer ligand for specific targeting and EVs for efficient membrane fusion, EGFRapt-pRNA-3WJ RNP was constructed and anchored onto EVs loaded with survivin siRNA. In the preliminary animal tests, systemic administration of the EV-siSurvivin coated with EGFRapt-pRNA-3WJ RNP inhibited tumor growth in orthotopic breast cancer xenograft mouse model by successfully downregulating the Survivin expression. The studies are indicative of the clinical benefit of FA-3WJ RNP based tumor targeting and gene therapy for the successful targeted therapy of primary and recurrent glioblastoma.from ! ORL Sfakianakis via paythelady.61 on Inoreader http://ift.tt/2hH3kTF
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,