J Nucl Med. 2016 Feb;57(2):279-84. doi: 10.2967/jnumed.115.163006.

Dynamic In Vivo SPECT Imaging of Neural Stem Cells Functionalized with Radiolabeled Nanoparticles for Tracking of Glioblastoma.

Cheng SH1, Yu D2, Tsai HM1, Morshed RA2, Kanojia D2, Lo LW3, Leoni L1, Govind Y2, Zhang L2, Aboody KS4, Lesniak MS2, Chen CT5, Balyasnikova IV6.
  • 1Department of Radiology, The University of Chicago, Chicago, Illinois.
  • 2The Brain Tumor Center, The University of Chicago, Chicago, Illinois.
  • 3Department of Radiology, The University of Chicago, Chicago, Illinois Institute of Biomedical Engineering and Nanomedicine, National Health Research Institute(s), Taiwan; and.
  • 4Department of Neuroscience, City of Hope National Medical Center and Beckman Research Institute, Duarte, California.
  • 5Department of Radiology, The University of Chicago, Chicago, Illinois irinabal@northwestern.edu cchen3@uchicago.edu.
  • 6The Brain Tumor Center, The University of Chicago, Chicago, Illinois irinabal@northwestern.edu cchen3@uchicago.edu.

 

Abstract

There is strong clinical interest in using neural stem cells (NSCs) as carriers for targeted delivery of therapeutics to glioblastoma. Multimodal dynamic in vivo imaging of NSC behaviors in the brain is necessary for developing such tailored therapies; however, such technology is lacking. Here we report a novel strategy for mesoporous silica nanoparticle (MSN)-facilitated NSC tracking in the brain via SPECT.

METHODS:

(111)In was conjugated to MSNs, taking advantage of the large surface area of their unique porous feature. A series of nanomaterial characterization assays was performed to assess the modified MSN. Loading efficiency and viability of NSCs with (111)In-MSN complex were optimized. Radiolabeled NSCs were administered to glioma-bearing mice via either intracranial or systemic injection. SPECT imaging and bioluminescence imaging were performed daily up to 48 h after NSC injection. Histology and immunocytochemistry were used to confirm the findings.

RESULTS:

(111)In-MSN complexes show minimal toxicity to NSCs and robust in vitro and in vivo stability. Phantom studies demonstrate feasibility of this platform for NSC imaging. Of significance, we discovered that decayed (111)In-MSN complexes exhibit strong fluorescent profiles in preloaded NSCs, allowing for ex vivo validation of the in vivo data. In vivo, SPECT visualizes actively migrating NSCs toward glioma xenografts in real time after both intracranial and systemic administrations. This is in agreement with bioluminescence live imaging, confocal microscopy, and histology.

CONCLUSION:

These advancements warrant further development and integration of this technology with MRI for multimodal noninvasive tracking of therapeutic NSCs toward various brain malignancies.

KEYWORDS: SPECT; cell tracking; glioma; nanoparticle; neural stem cells

PMID: 26564318

 

Supplement:

There is great interest in utilizing adult stem cells as therapeutic carriers for the treatment of brain malignancies due to their ability to migrate, carry therapeutic payload, and regenerate. Bone-marrow  and adipose tissue-derived mesenchymal stem cells, neural stem cells, and induced progenitor stem cells are all being evaluated in the context of brain tumors and other disorders of the central nervous system (CNS)[1, 2]. Pre-clinical studies investigating a clonal human neural stem cell (NSC) line, HB1.F3.CD, for glioma tropism, distribution in the brain and tumor tissue after local and systemic delivery, safety, and therapeutic efficacy have led to the approval of these cells for phase I clinical trials in patients with recurrent high-grade glioma (NCT01172964). Modalities for tracking the fate of stem cells are critical for the development of efficient stem cell-based therapies for glioma and other brain malignancies.  However, tracking stem cells in the CNS is far from a trivial task.  Currently, MRI imaging of iron-labeled stem cells is the gold standard for imaging transplanted stem cells in the brain, but this method has inherent limitations, such as false positive signals arising from macrophage engulfment of imaging vehicles, small hemorrhages, or iron depositions in aging or degenerating brains [3-6]. These limitations demonstrate the unmet need for alternative imaging modalities to trace stem cells in the brain. In this study, we have reported that a nano-platform can be utilized to label NSCs with a SPECT radiotracer, 111Indium (111In). Mesoporous silica nanoparticles (MSN) were conjugated with 111In, and were used to label NSCs in non-toxic amounts. We demonstrated that the migration of radiolabeled stem cells towards intracranial glioblastoma xenografts can be tracked with SPECT imaging in the brain after both local and systemic injections in an experimental animal model of glioblastoma (Figure 1). SPECT stem cell tracking in the brain can overcome limitations imposed by MRI, such as the similarity of signal generated by iron-labeled stem cells and blood deposits, and provide good spatial resolution and sensitivity. Concerning the latter, we have previously reported that a sub-500μm resolution could be achieved with SPECT imaging, and the signal corresponding to as low as 750  125I-labeled T cells could be visualized in the brain [7]. The further development of sensitive imaging methods for stem cells could uncover information about the behavior of stem cells in relation to brain malignancies, an otherwise difficult challenge with existing, traditional approaches.  Although the focus of our study is to validate the tracking of stem cells using SPECT, this approach serves as the foundation for the development of dual imaging strategies poised to overcome limitations of each method on its own. For example, a large surface area of MSN can be labeled with contrast agents suitable for both MRI and SPECT imaging.  MRI imaging can provide anatomical details regarding the location of tumors and stem cells, and simultaneous SPECT imaging will allow for a better functional readout of dynamic of stem cell migration, distribution, and engraftment in the CNS and cancerous tissue. The dual approach could also correlate the outcome in stem-cell based therapeutic approaches with these parameters.  Finally, our study suggests that this nanoparticle-based, non-invasive, in vivo imaging platform could be helpful in further advancing stem cells in clinical practice by improving our understanding of their behaviors in pre-clinical models of glioblastoma and other brain malignancies.

 

 

fig1

Figure 1. SPECT imaging allows the tracing of NSCs loaded with 111In-labeled mesoporous nanoparticles to glioblastoma xenograft after systemic and local delivery in an experimental model of disease.   Illustrated by Michael Gallagher, Department of Neurological Surgery, Northwestern University

 

 

Contact:

Chin-Tu Chen, Ph.D.                                                                                  

Associate Professor

Dept. of Radiology

Pritzker School of Medicine

University of Chicago

5841 S. Maryland Ave,

Chicago, IL 60637

Office: 773.702.6269

c-chen@uchicago.edu

 

Irina V. Balyasnikova PhD.

Associate Professor

Dept. of Neurological Surgery

Feinberg School of Medicine

Northwestern University

303 E. Superior St. Room 3-113

Chicago, IL 60611

Office: 312.503.4868

irinabal@northwestern.edu

 

References

  1. Young, J.S., et al., Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy. Expert Opin Drug Deliv, 2014. 11(11): p. 1733-46.
  2. Shah, K., Stem cell-based therapies for tumors in the brain: are we there yet? Neuro Oncol, 2016. 18(8): p. 1066-78.
  3. Gu, E., et al., Molecular imaging of stem cells: tracking survival, biodistribution, tumorigenicity, and immunogenicity. Theranostics, 2012. 2(4): p. 335-45.
  4. Kurpisz, M., et al., Bone marrow stem cell imaging after intracoronary administration. Int J Cardiol, 2007. 121(2): p. 194-5.
  5. Pawelczyk, E., et al., In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: implications for cellular therapy. Stem Cells, 2008. 26(5): p. 1366-75.
  6. Brass, S.D., et al., Magnetic resonance imaging of iron deposition in neurological disorders. Top Magn Reson Imaging, 2006. 17(1): p. 31-40.
  7. Meng, L.J., et al., An Ultrahigh Resolution SPECT System for I-125 Mouse Brain Imaging Studies. Nucl Instrum Methods Phys Res A, 2009. 600(1): p. 498-505.

 

 

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