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Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande Velde G, Lambrichts I, Van Der Linden A, Verfaillie CM, Himmelreich U - Stem Cell Res Ther (2015)

Bottom Line: Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging.

View Article: PubMed Central - PubMed

Affiliation: Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.

ABSTRACT

Introduction: In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.

Methods: Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).

Results: In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.

Conclusions: Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.

No MeSH data available.


Related in: MedlinePlus

In vitro validation of SPIO labeling of mOct4− BM-MAPCs. a ICP-OES data showed superior labeling of mOct4− BM-MAPCs using ihSPIO particles compared to labeling using Endorem® with unlabeled cells containing 1.3 ± 0.8 pg Fe/cell, ihSPIO-labeled mOct4- BM-MAPCs containing 15.9 ± 1.5 pg Fe/cell and Endorem®-labeled mOct4− BM-MAPCs 8.2 ± 0.6 pg Fe/cell. b An MRI phantom confirmed these results and showed the corresponding in vitro contrast generation caused by the presence of iron in the cells with enhanced signal decay corresponding to higher concentrations of iron/cell. c BLI using D-Luciferin as a substrate indicated no marked differences in cell viability between labeled and unlabeled cells. SMG2-mPEGSI second seed mediated growth-mPolyethylene glycol
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Fig1: In vitro validation of SPIO labeling of mOct4− BM-MAPCs. a ICP-OES data showed superior labeling of mOct4− BM-MAPCs using ihSPIO particles compared to labeling using Endorem® with unlabeled cells containing 1.3 ± 0.8 pg Fe/cell, ihSPIO-labeled mOct4- BM-MAPCs containing 15.9 ± 1.5 pg Fe/cell and Endorem®-labeled mOct4− BM-MAPCs 8.2 ± 0.6 pg Fe/cell. b An MRI phantom confirmed these results and showed the corresponding in vitro contrast generation caused by the presence of iron in the cells with enhanced signal decay corresponding to higher concentrations of iron/cell. c BLI using D-Luciferin as a substrate indicated no marked differences in cell viability between labeled and unlabeled cells. SMG2-mPEGSI second seed mediated growth-mPolyethylene glycol

Mentions: eGFP-fLuc-HSV-TK-expressing mOct4− BM-MAPCs [26] were labeled with ihSPIO particles [31] or Endorem® after which characterization was performed using ICP-OES, MRI and BLI (Fig. 1). ICP-OES (Fig. 1a) showed an iron uptake of 15.9 ± 1.5 pg iron/cell for ihSPIO-labeled cells compared to 8.2 ± 0.6 pg iron/cell for Endorem®-labeled cells. Using optimized labeling conditions, in vitro cell labeling with ihSPIO-labeled cells showed high contrast (low signal intensity) on MRI (Fig. 1b) and no marked differences in cell viability when comparing labeled and unlabeled cells as assessed by BLI (Fig. 1c). Considering that only 1–2 pg iron are needed for cell imaging, these results indicate that, for both contrast agents, single cell visualization in vitro is in principle feasible and safe [34].Fig. 1


Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande Velde G, Lambrichts I, Van Der Linden A, Verfaillie CM, Himmelreich U - Stem Cell Res Ther (2015)

In vitro validation of SPIO labeling of mOct4− BM-MAPCs. a ICP-OES data showed superior labeling of mOct4− BM-MAPCs using ihSPIO particles compared to labeling using Endorem® with unlabeled cells containing 1.3 ± 0.8 pg Fe/cell, ihSPIO-labeled mOct4- BM-MAPCs containing 15.9 ± 1.5 pg Fe/cell and Endorem®-labeled mOct4− BM-MAPCs 8.2 ± 0.6 pg Fe/cell. b An MRI phantom confirmed these results and showed the corresponding in vitro contrast generation caused by the presence of iron in the cells with enhanced signal decay corresponding to higher concentrations of iron/cell. c BLI using D-Luciferin as a substrate indicated no marked differences in cell viability between labeled and unlabeled cells. SMG2-mPEGSI second seed mediated growth-mPolyethylene glycol
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4562202&req=5

Fig1: In vitro validation of SPIO labeling of mOct4− BM-MAPCs. a ICP-OES data showed superior labeling of mOct4− BM-MAPCs using ihSPIO particles compared to labeling using Endorem® with unlabeled cells containing 1.3 ± 0.8 pg Fe/cell, ihSPIO-labeled mOct4- BM-MAPCs containing 15.9 ± 1.5 pg Fe/cell and Endorem®-labeled mOct4− BM-MAPCs 8.2 ± 0.6 pg Fe/cell. b An MRI phantom confirmed these results and showed the corresponding in vitro contrast generation caused by the presence of iron in the cells with enhanced signal decay corresponding to higher concentrations of iron/cell. c BLI using D-Luciferin as a substrate indicated no marked differences in cell viability between labeled and unlabeled cells. SMG2-mPEGSI second seed mediated growth-mPolyethylene glycol
Mentions: eGFP-fLuc-HSV-TK-expressing mOct4− BM-MAPCs [26] were labeled with ihSPIO particles [31] or Endorem® after which characterization was performed using ICP-OES, MRI and BLI (Fig. 1). ICP-OES (Fig. 1a) showed an iron uptake of 15.9 ± 1.5 pg iron/cell for ihSPIO-labeled cells compared to 8.2 ± 0.6 pg iron/cell for Endorem®-labeled cells. Using optimized labeling conditions, in vitro cell labeling with ihSPIO-labeled cells showed high contrast (low signal intensity) on MRI (Fig. 1b) and no marked differences in cell viability when comparing labeled and unlabeled cells as assessed by BLI (Fig. 1c). Considering that only 1–2 pg iron are needed for cell imaging, these results indicate that, for both contrast agents, single cell visualization in vitro is in principle feasible and safe [34].Fig. 1

Bottom Line: Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging.

View Article: PubMed Central - PubMed

Affiliation: Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.

ABSTRACT

Introduction: In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.

Methods: Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).

Results: In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.

Conclusions: Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.

No MeSH data available.


Related in: MedlinePlus