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

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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Tong, Wing Yin ; Alnakhli, Mohammed ; Bhardwaj, Richa ; Apostolou, Sinoula ; Sinha, Sougata ; Fraser, Cara ; Kuchel, Tim ; Kuss, Bryone ; Voelcker, Nicolas H. / Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma. In: Journal of Nanobiotechnology. 2018 ; Vol. 16, No. 1.
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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.",
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Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma. / Tong, Wing Yin; Alnakhli, Mohammed; Bhardwaj, Richa; Apostolou, Sinoula; Sinha, Sougata; Fraser, Cara; Kuchel, Tim; Kuss, Bryone; Voelcker, Nicolas H.

In: Journal of Nanobiotechnology, Vol. 16, No. 1, 38, 13.04.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma

AU - Tong, Wing Yin

AU - Alnakhli, Mohammed

AU - Bhardwaj, Richa

AU - Apostolou, Sinoula

AU - Sinha, Sougata

AU - Fraser, Cara

AU - Kuchel, Tim

AU - Kuss, Bryone

AU - Voelcker, Nicolas H.

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AB - 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.

KW - Brain tumour

KW - Cell proliferation

KW - Gene delivery

KW - Multidrug resistance-associated protein

KW - Nanoparticles

KW - SiRNA

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