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

27 Citations (Scopus)

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 (US)
Pages (from-to)53-66
Number of pages14
JournalBiomaterials
Volume100
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein 4
Stem cells
Mesenchymal Stromal Cells
Brain Neoplasms
Tumors
Brain
Nanoparticles
Bone
Proteins
Survival
Neoplastic Stem Cells
Glioma
Bearings (structural)
Nanobiotechnology
Nude Rats
Gene therapy
Tropism
Therapeutic Uses
Cell- and Tissue-Based Therapy
Blood-Brain Barrier

Keywords

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

ASJC Scopus subject areas

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

Cite this

Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. / Mangraviti, Antonella; Tzeng, Stephany Y.; Gullotti, David; Kozielski, Kristen L.; Kim, Jennifer E.; Seng, Michael; Abbadi, Sara; Schiapparelli, Paula; Sarabia Estrada, Rachel; Vescovi, Angelo; Brem, Henry; Olivi, Alessandro; Tyler, Betty; Green, Jordan J.; Quinones-Hinojosa, Alfredo.

In: Biomaterials, Vol. 100, 01.09.2016, p. 53-66.

Research output: Contribution to journalArticle

Mangraviti, A, Tzeng, SY, Gullotti, D, Kozielski, KL, Kim, JE, Seng, M, Abbadi, S, Schiapparelli, P, Sarabia Estrada, R, Vescovi, A, Brem, H, Olivi, A, Tyler, B, Green, JJ & Quinones-Hinojosa, A 2016, 'Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival', Biomaterials, vol. 100, pp. 53-66. https://doi.org/10.1016/j.biomaterials.2016.05.025
Mangraviti, Antonella ; Tzeng, Stephany Y. ; Gullotti, David ; Kozielski, Kristen L. ; Kim, Jennifer E. ; Seng, Michael ; Abbadi, Sara ; Schiapparelli, Paula ; Sarabia Estrada, Rachel ; Vescovi, Angelo ; Brem, Henry ; Olivi, Alessandro ; Tyler, Betty ; Green, Jordan J. ; Quinones-Hinojosa, Alfredo. / Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival. In: Biomaterials. 2016 ; Vol. 100. pp. 53-66.
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AU - Kim, Jennifer E.

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AU - Abbadi, Sara

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AU - Vescovi, Angelo

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