TY - JOUR
T1 - Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival
AU - Mangraviti, Antonella
AU - Tzeng, Stephany Y.
AU - Gullotti, David
AU - Kozielski, Kristen L.
AU - Kim, Jennifer E.
AU - Seng, Michael
AU - Abbadi, Sara
AU - Schiapparelli, Paula
AU - Sarabia-Estrada, Rachel
AU - Vescovi, Angelo
AU - Brem, Henry
AU - Olivi, Alessandro
AU - Tyler, Betty
AU - Green, Jordan J.
AU - Quinones-Hinojosa, Alfredo
N1 - Publisher Copyright:
© 2016 Elsevier Ltd.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - Adipose-derived stem cells
KW - Brain cancer
KW - Gene delivery
KW - Nanoparticles
KW - Tumor stem cells
UR - http://www.scopus.com/inward/record.url?scp=84970016337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84970016337&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2016.05.025
DO - 10.1016/j.biomaterials.2016.05.025
M3 - Article
C2 - 27240162
AN - SCOPUS:84970016337
SN - 0142-9612
VL - 100
SP - 53
EP - 66
JO - Biomaterials
JF - Biomaterials
ER -