MRI visualization of neural stem cells targeting human glioma in an orthotopic mouse model

A52

Neural stem cells (NSC) display inherent tumor-tropic properties to primary and metastatic tumor foci, providing the basis for development of a novel treatment approach. We postulate that tumor-selective NSC-mediated delivery can maximize local concentrations of anti-cancer agents, while minimizing toxicity to normal tissues and overcoming some of the limitations of the currently available conventional therapies. Our pre-clinical data has demonstrated tumor-tropism of NSCs regardless of route of administration. A multi-potent NSC line, HB1.F3 has demonstrated promising therapeutic potential in animal models of glioblastoma, melanoma brain metastases, medulloblastoma, as well as stroke, Parkinson’s disease, Huntington’s and lysosomal storage disease. A means to monitor tumor targeting, distribution and fate of NSCs in vivo will allow us to determine optimal treatment paradigm and regimens to develop future patient trials. Recent developments have shown that magnetically-labeled cells can be tracked in iron sensitive T2-weighted MRI as hypo-intense signals. Here, we demonstrate that HB1.F3 (parental line) and HB1.F3.CD (expressing cytosine deaminase, a prodrug-activating enzyme) NSCs can be efficiently labeled with iron oxide nanoparticles, Ferumoxide (FE), complexed to Protamine Sulfate (Pro) and visualized using MRI. We also assess the potential toxicity of FE-Pro complex in our parental and therapeutic NSCs in vitro. No significant alterations in NSC viability and proliferation were observed during 8 days after FE-Pro labeling (~5-6 cell divisions). Furthermore, the tumor-tropic properties of FE-Pro-labeled NSCs were also retained both in vitro and in vivo. FE-Pro-labeled NSCs, when injected contra-lateral to human glioma implant (U251) in mouse brain, were detected as low intensity T2-weighted MRI signal at the NSC injection site, as well as at the tumor site. The MRI data were confirmed by histological evaluation. Our data support the feasibility of cellular MRI for monitoring of stem cell targeting of tumors, and may aid translation of such therapy to clinical trials in patients with glioma.