SC-17 * BMP4-SECRETING hAdMSCs ENGINEERED WITH NANOPARTICLES: A NON-VIRAL MSC-BASED THERAPY FOR GLIOBLASTOMA
Year: 2014
Type: article
Abstract: Mesenchymal stem cells (MSCs) have attracted significant attention as effective delivery vehicles for targeting brain disorders. We have shown that MSCs derived from human adipose tissue (hAMSCs) and genetically modified with viruses display high anti-glioma tropism and can deliver bone morphogenetic protein 4 (BMP4), a therapeutic agent that reduces the clonogenic ability of glioma stem cells. Virus-safety concerns have led to the development of biodegradable nanoparticles that can transfect human cells. We identify nanoparticles for engineering hAMCSs to secrete BMP4 both in vitro and in vivo to treat brain cancer. hAMSCs were transfected using poly (beta-amino ester-PBAE)-based nanoparticles. Transfection efficacy and toxicity were evaluated to determine the optimal formulation to transfect hAMSCs with a BMP4-expressing plasmid. In vitro functional assays evaluated the effect of the transfection on hAMSC phenotype. In vivo imaging and histological analyses tracked engineered hAMSCs (NP-AMSCs) in the brain after local and systemic administration to rodents with orthotopic human tumors. Optimized nanoparticles transfected hAMSCs with 75 ± 2% efficacy and 71 ± 7% viability which was significantly superior (p < 0.0001) to LipofectamineTM 2000(16 ± 3% transfection, 54 ± 5% viability) the leading commercial product. PCR and Western blot analysis confirmed BMP4 production from NP-hAMSCs (52.5 ng protein/106 NP-hAMSCs). NP-hAMSCs were significantly better in migration and invasion (p = 0.005) than hAMSCs transduced with lentivirus. Flow cytometry showed that NP-hAMSCs retain multipotency. Intranasal, intravenous, and local delivery of luciferase- and GFP-expressing NP-hAMSCs in a rodent model of human glioma showed transgene expression 5 days after injection and NP-hAMSC migration towards the brain and within the tumor. We demonstrate that PBAE-nanoparticle formulations effectively transfect hAMSCs to produce BMP4. NP-AMSCs migrate towards the brain and penetrate the tumor in a model of human glioma after local and systemic administration. NP-engineered BMP4-secreting hAMSCs can be a safe and effective alternative to viral transduction for stem cell-based anti-glioma gene therapies.
Source: Neuro-Oncology
Institutions: Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2314433142