Abstract
Mesenchymal stem cells (MSCs) hold tremendous potential as a targeted cell-based delivery platform for inflammatory and cancer therapy. Genetic manipulation of MSCs, however, is challenging, and therefore, most studies using MSCs as therapeutic cell carriers have utilized viral vectors to transduce the cells. Here, we demonstrate, for the first time, an alternative approach for the efficient transfection of MSCs; therapeutic ultrasound (TUS). Using TUS with low intensities and moderate frequencies, MSCs were transfected with a pDNA encoding for PEX, a protein that inhibits tumor angiogenesis, and studied as a cell vehicle for in vivo tumor therapy. TUS application did not alter the MSCs’ stemness or their homing capabilities, and the transfected MSCs transcribed biologically active PEX. Additionally, in a mouse model, 70% inhibition of prostate tumor growth was achieved following a single I.V. administration of MSCs that were TUS-transfected with pPEX. Further, the repeated I.V. administration of TUS-pPEX transfected-MSCs enhanced tumor inhibition up to 84%. Altogether, these results provide a proof of concept that TUS-transfected MSCs can be effectively used as a cell-based delivery approach for the prospective treatment of cancer.
Highlights
In the current study, we assessed the feasibility of therapeutic ultrasound (TUS) as a potentially safe and efficient method to transfect Mesenchymal stem cells (MSCs) with plasmid DNA (pDNA) encoding for an inhibitor of tumor angiogenesis, and to produce a cell vehicle for in vivo tumor therapy
Conditioned media harvested from TUS-transfected MSCs, non-transfected MSCs or MSCs incubated with pDNA-pDNA encoding for hemopexin-like domain fragment (PEX) without TUS application were assessed for the presence of PEX protein using Enzyme-linked immunosorbent assay (ELISA)
The PEX expression level in TUS-transfected MSCs without ultrasound contrast agents (USCAs) was significantly higher than the controls (p < 0.001)
Summary
We assessed the feasibility of therapeutic ultrasound (TUS) as a potentially safe and efficient method to transfect MSCs with pDNA encoding for an inhibitor of tumor angiogenesis, and to produce a cell vehicle for in vivo tumor therapy. We previously reported the application of TUS to directly deliver pDNA encoding for hemopexin-like domain fragment (PEX) to tumors in vivo, thereby demonstrating the efficacy of TUS as a non-viral gene delivery technology[17]. PEX interacts with the endothelial cell’s αvβ[3] integrin, and by this, serves as a natural inhibitor of MMP-2. It simultaneously inhibits angiogenesis, cell proliferation, and migration in vitro and in vivo[18,19]. The effect of TUS-pPEX transfected-MSCs on tumor growth was studied as well as their repeated administration to mice bearing prostate tumors
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