Mariarosa Mazza1, Hassan Ahmad1, Marilena Hadjidemetriou1, Giulia Agliardi1, Omar N Pathmanaban2, Andrew T King2, Brian W Bigger3, Sandra Vranic1,4, Kostas Kostarelos1,4. 1. Nanomedicine Lab, Faculty of Biology, Medicine & Health, The University of Manchester, AV Hill Building, Manchester, M13 9PT, UK. 2. Department of Neurosurgery, Salford Royal Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester, M6 8HD, UK. 3. Stem Cell & Neurotherapies Group, School of Biological Sciences, Faculty of Biology Medicine & Health, Division of Cell Matrix Biology & Regenerative Medicine, University of Manchester, Manchester, M13 9PT, UK. 4. National Graphene Institute, The University of Manchester, Booth Street East, Manchester, M13 9PL, UK.
Abstract
Aim: To develop a nonviral tool for the delivery of siRNA to brain tumor cells using peptide nanofibers (PNFs). Materials & methods: Uptake of PNFs was evaluated by confocal microscopy and flow cytometry. Gene silencing was determined by RT-qPCR and cell invasion assay. Results: PNFs enter phagocytic (BV-2) and nonphagocytic (U-87 MG) cells via endocytosis and passive translocation. siPLK1 delivered using PNFs reduced the expression of polo-like kinase 1 mRNA and induced cell death in a panel of immortalized and glioblastoma-derived stem cells. Moreover, targeting MMP2 using PNF:siMMP2 reduced the invasion capacity of U-87 MG cells. We show that stereotactic intra-tumoral administration of PNF:siPLK1 significantly extends the survival of tumor bearing mice comparing with the untreated tumor bearing animals. Conclusion: Our results suggest that this nanomedicine-based RNA interference approach deserves further investigation as a potential brain tumor therapeutic tool.
Aim: To develop a nonviral tool for the delivery of siRNA to brain tumor cells using peptide nanofibers (PNFs). Materials & methods: Uptake of PNFs was evaluated by confocal microscopy and flow cytometry. Gene silencing was determined by RT-qPCR and cell invasion assay. Results: PNFs enter phagocytic (BV-2) and nonphagocytic (U-87 MG) cells via endocytosis and passive translocation. siPLK1 delivered using PNFs reduced the expression of polo-like kinase 1 mRNA and induced cell death in a panel of immortalized and glioblastoma-derived stem cells. Moreover, targeting MMP2 using PNF:siMMP2 reduced the invasion capacity of U-87 MG cells. We show that stereotactic intra-tumoral administration of PNF:siPLK1 significantly extends the survival of tumor bearing mice comparing with the untreated tumor bearing animals. Conclusion: Our results suggest that this nanomedicine-based RNA interference approach deserves further investigation as a potential brain tumor therapeutic tool.
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