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

doi:10.1016/j.biomaterials.2016.05.025

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

Biomaterials. 2016 Sep:100:53-66. doi: 10.1016/j.biomaterials.2016.05.025. Epub 2016 May 21.

Authors

Affiliations

¹ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, viale dei Cappuccini, 1, 71013 S. Giovanni Rotondo, Italy.
⁵ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: btyler@jhmi.edu.
⁷ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: green@jhu.edu.
⁸ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: aquinon2@jhmi.edu.

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.

Keywords: Adipose-derived stem cells; Brain cancer; Gene delivery; Nanoparticles; Tumor stem cells.

MeSH terms

Adipose Tissue / cytology
Animals
Bone Morphogenetic Protein 4 / genetics*
Brain Neoplasms / therapy*
Cell Line
Cell Line, Tumor
DNA / administration & dosage*
DNA / genetics
Female
Genetic Engineering* / methods
Humans
Mesenchymal Stem Cell Transplantation* / methods
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / metabolism*
Nanoparticles / chemistry
Polymers / chemistry
Rats
Rats, Nude
Transfection* / methods

Substances

BMP4 protein, human
Bone Morphogenetic Protein 4
Polymers
poly(beta-amino ester)
DNA

Abstract

MeSH terms

Substances

Grants and funding