Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival

Antonella Mangraviti, Stephany Y. Tzeng, David Gullotti, Kristen L. Kozielski, Jennifer E. Kim, Michael Seng, Sara Abbadi, Paula Schiapparelli, Rachel Sarabia-Estrada, Angelo Vescovi, Henry Brem, Alessandro Olivi, Betty Tyler, Jordan J. Green, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

Abstract

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies.

Original languageEnglish
Pages (from-to)53-66
Number of pages14
JournalBiomaterials
Volume100
DOIs
Publication statusPublished - Sep 1 2016

Keywords

  • Adipose-derived stem cells
  • Brain cancer
  • Gene delivery
  • Nanoparticles
  • Tumor stem cells

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

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  • Cite this

    Mangraviti, A., Tzeng, S. Y., Gullotti, D., Kozielski, K. L., Kim, J. E., Seng, M., Abbadi, S., Schiapparelli, P., Sarabia-Estrada, R., Vescovi, A., Brem, H., Olivi, A., Tyler, B., Green, J. J., & Quinones-Hinojosa, A. (2016). Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. Biomaterials, 100, 53-66. https://doi.org/10.1016/j.biomaterials.2016.05.025