Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma

Wing Tong, Mohammed Alnakhli, Richa Bhardwaj, Sinoula Apostolou, Sougata Sinha, Cara Fraser, Tim Kuchel, Bryone Kuss, Nicolas Voelcker

    Research output: Contribution to journalArticlepeer-review

    67 Citations (Scopus)

    Abstract

    Background: Multidrug resistance-associated protein 1 (MRP1) overexpression plays a major role in chemoresistance in glioblastoma multiforme (GBM) contributing to its notorious deadly nature. Although MRP1-siRNA transfection to GBM in vitro has been shown to sensitise the cells to drug, MRP1 silencing in vivo and the phenotypic influence on the tumour and normal tissues upon MRP1 down-regulation have not been established. Here, porous silicon nanoparticles (pSiNPs) that enable high-capacity loading and delivery of siRNA are applied in vitro and in vivo. Result: We established pSiNPs with polyethyleneimine (PEI) capping that enables high-capacity loading of siRNA (92 μg of siRNA/mg PEI-pSiNPs), and optimised release profile (70% released between 24 and 48 h). These pSiNPs are biocompatible, and demonstrate cellular uptake and effective knockdown of MRP1 expression in GBM by 30%. Also, siRNA delivery was found to significantly reduce GBM proliferation as an associated effect. This effect is likely mediated by the attenuation of MRP1 transmembrane transport, followed by cell cycle arrest. MRP1 silencing in GBM tumour using MRP1-siRNA loaded pSiNPs was demonstrated in mice (82% reduction at the protein level 48 h post-injection), and it also produced antiproliferative effect in GBM by reducing the population of proliferative cells. These results indicate that in vitro observations are translatable in vivo. No histopathological signs of acute damage were observed in other MRP1-expressing organs despite collateral downregulations. Conclusions: This study proposes the potential of efficient MRP1-siRNA delivery by using PEI-capped pSiNPs in achieving a dual therapeutic role of directly attenuating the growth of GBM while sensitising residual tumour cells to the effects of chemotherapy post-resection.

    Original languageEnglish
    Article number38
    Number of pages17
    JournalJOURNAL OF NANOBIOTECHNOLOGY
    Volume16
    Issue number1
    DOIs
    Publication statusPublished - 13 Apr 2018

    Keywords

    • Brain tumour
    • Cell proliferation
    • Gene delivery
    • Multidrug resistance-associated protein
    • Nanoparticles
    • SiRNA

    Fingerprint

    Dive into the research topics of 'Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma'. Together they form a unique fingerprint.

    Cite this