Development of real-time MR cell tracking for human neural stem/progenitor cell-mediated brain tumor therapy Free

A46

Gliomablastoma multiforme (GBM), the most aggressive type of brain tumor, remains a challenge to treat, with a dismal prognosis of less than one year following diagnosis. The highly invasive nature of these tumor cells contributes to disease recurrence and lethality, and is the major factor contributing to treatment failure. We and others have demonstrated the tumor tropism of neural stem cell (NSCs), and their use as a cellular delivery vehicles to effectively target therapeutics to these invasive tumor cells throughout the brain. 70-90% therapeutic efficacy has been reported with NSC-mediated treatment paradigms in several primary and metastatic tumor models inclulding glioma, medulloblastoma, melanoma brain metastases, and neuroblastoma. The ability to non-invasively monitor dynamic spatiotemporal patterns of NSC tumor targeting in real-time will allow optimization of treatment strategies with clinical promise. Here, we demonstrated that FE-Pro labeled human NSCs, HB1.F3 clonal line, in development for glioma patient trials, can be visualized by cellular MRI in orthotopic glioma (human U-251) xenograft mouse models. We report no significant changes in HB1.F3 cellular viability, proliferation, migratory properties or transgene expression, by the MRI contrast agent used in the study - individually FDA-approved Ferumoxide (FE) and Protamine Sulfate (Pro) complex. FE-Pro labeled NSCs were detected by MRI as hypointense signals at tumor site within 4 days after intracranial administration directly caudal-lateral to or in the opposite hemisphere from tumor site. Sensitivity of MRI was established at as few as 600 FE-Pro NSCs in each MRI brain slice (76 µm/pixel). These results support use of this nano-particle cellular tracking method in initial trials of NSC-mediated glioma therapy, which would greatly enhance the data that would be obtained, including NSC-tumor distribution over time - in order to optimize timing of therapeutic delivery.