ATPS-90: EFFICACY OF NON-VIRAL ENGINEERED ADIPOSE MESENCHYMAL STEM CELLS FOR BRAIN TUMOR THERAPY

Human adipose derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and have been found to be effective as delivery vehicles for targeting brain tumors. Their application, however, has been limited by safety concerns regarding genetic modifications associated with the use of viral vectors. This study developed non-viral, biodegradable nanoparticles to transfect hAMSCs safely and efficiently. We evaluated their efficacy to deliver a bone morphogenetic protein 4 (BMP4), a therapeutic human Brain Tumor Initiating Cells (BTIC)-targeting gene that reduces the clonogenic ability of glioma stem cells, in a human primary malignant glioma model. We optimized a poly (beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with a BMP4-expressing plasmid (NP-hAMSCs), having a transfection efficacy and safety profile superior (p < 0.0001) to Lipofectamine™ 2000. NP-hAMSCs engineered with the PBAE polymer to produce BMP4 (BMP4/NP-hAMSCs) maintained their multi-potency as well as their migration and invasion capacities significantly better than hAMSCs transduced with lentivirus (p = 0.005). Moreover, NP-hAMSC producing BMP4 maintained its pro-differentiation effect on BTICs and significantly inhibited their oncosphere-forming capacity (p < 0.0001). In vivo imaging and histological analyses were conducted to monitor NP-AMSCs administered locally and systemically into the brain of rodents bearing orthotopic human tumors. Intranasal, intravenous, and local delivery of luciferase- and GFP-expressing NP-hAMSCs showed successful migration to the brain and effective transgene expression in the tumor after both systemic and local administration. Finally, twenty-four athymic rats were inoculated with primary BTICs and treated with BMP4-producing NP-AMSCs via intranasal administration and intravenous administration. The animals treated with intranasal administration showed a significant benefit in survival (p = 0.02 vs. control). This study highlights a safe and effective alternative to viral transduction for stem cell-based gene therapies. NP-engineered hAMSCs represents a novel nanomedicine approach to produce and deliver BTIC-targeting genes for brain tumor treatment.