Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Dou Yu, Omar F. Khan, Mario L. Suvà, Biqin Dong, Wojciech K. Panek, Ting Xiao, Meijing Wu, Yu Han, Atique U. Ahmed, Irina V. Balyasnikova, Hao F. Zhang, Cheng Sun, Robert Langer, Daniel G. Anderson, Maciej S. Lesniak

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

Original languageEnglish (US)
Pages (from-to)E6147-E6156
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number30
DOIs
StatePublished - Jul 25 2017

Funding

We thank Dr. Thomas J. Hope of Northwestern University for generous support with the LiCOR system; Dr. C. David James and Dr. Shi-Yuan Cheng at Northwestern University and Dr. Ichiro Nakano from the University of Alabama at Birmingham for the generous gift of patient-derived GBM cells; Dr. Vytas Bindokas at The University of Chicago Integrated Light Microscopy Core for guidance and advice in imaging applications; Paul Mehl, Carolina Ostiguin, and Dr. Suchitra Swaminathan at the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core and Drs. Wensheng Liu, Joshua Rappoport, and Constadina Arvanitis for microscopy, bioluminescence imaging, and laser-capture microdissection at the Northwestern University Center for Advanced Microscopy (generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center). This work was supported by NIH Grant R35CA197725 (to M.S.L.), a Burroughs Wellcome Collaborative Travel Grant (to D.Y.), an Elsa U. Pardee Foundation Grant (to D.Y.), and a Northwestern University I3 Pilot Grant (to C.S., M.S.L., and D.Y.).

Keywords

  • Brain tumor-initiating cells
  • Convection-enhanced delivery
  • Glioblastoma transcription factor
  • Lipopolymeric nanoparticle
  • SiRNA

ASJC Scopus subject areas

  • General

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