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Nanoparticle phagocytosis and cellular stress: involvement in cellular imaging and in gene therapy against glioma
Anne-Karine Bouzier-Sore1, Emeline Ribot, Véronique Bouchaud
1RMSB Center, Université de Bordeaux, Bordeaux Cedex, France. akb@rmsb.u-bordeaux2.fr
Abstract:
In gene therapy against glioma, targeting tumoral tissue is not an easy task. We used the tumor infiltrating property of microglia in this study. These cells are well adapted to this therapy since they can phagocyte nanoparticles and allow their visualization by MRI. Indeed, while many studies have used transfected microglia containing a suicide gene and other internalized nanoparticles to visualize microglia, none have combined both approaches during gene therapy. Microglia cells were transfected with the TK-GFP gene under the control of the HSP(70) promoter. First, the possible cellular stress induced by nanoparticle internalization was checked to avoid a non-specific activation of the suicide gene. Then, MR images were obtained on tubes containing microglia loaded with superparamagnetic nanoparticles (VUSPIO) to characterize their MR properties, as well as their potential to track cells in vivo. VUSPIO were efficiently internalized by microglia, were found non-toxic and their internalization did not induce any cellular stress. VUSPIO relaxivity r(2) was 224 mM(-1).s(-1). Such results could generate a very high contrast between loaded and unloaded cells on T(2)-weighted images. The intracellular presence of VUSPIO does not prevent suicide gene activity, since TK is expressed in vitro and functional in vivo. It allows MRI detection of gene modified macrophages during cell therapy strategies.
Insights
This study demonstrates that microglia can be engineered for glioma gene therapy. These modified cells, loaded with nanoparticles, are trackable by MRI and retain their therapeutic suicide gene function.
Area of Science:
- Neuroscience
- Oncology
- Biotechnology
Background:
- Targeting glioma with gene therapy is challenging due to difficulties in reaching tumor tissue.
- Microglia, immune cells within the brain, possess tumor-infiltrating properties and can phagocytose nanoparticles.
- Existing strategies often use microglia for either gene delivery or nanoparticle imaging, but not both simultaneously.
Purpose of the Study:
- To investigate the combined use of gene-modified microglia and superparamagnetic nanoparticles for glioma therapy and MRI tracking.
- To assess the safety and efficacy of VUSPIO-loaded, TK-GFP transfected microglia for in vivo cell tracking and therapeutic potential.
Main Methods:
- Microglia were transfected with the TK-GFP suicide gene under the HSP(70) promoter.
- The impact of VUSPIO nanoparticle internalization on cellular stress and suicide gene activation was evaluated.
- MRI properties of VUSPIO-loaded microglia were characterized, and their in vivo cell tracking potential was assessed.
Main Results:
- VUSPIO nanoparticles were efficiently internalized by microglia without inducing cellular stress or non-specific suicide gene activation.
- VUSPIO demonstrated high relaxivity (r(2) = 224 mM(-1).s(-1)), enabling high contrast imaging of loaded cells on T(2)-weighted MRI.
- Intracellular VUSPIO did not impede TK gene expression or function, allowing for MRI detection of gene-modified microglia in vivo.
Conclusions:
- This combined approach offers a promising strategy for targeted glioma gene therapy, leveraging microglia's natural properties.
- MRI tracking of VUSPIO-loaded, gene-modified microglia facilitates monitoring of cell delivery and distribution during therapy.
- The study validates the dual functionality of microglia as therapeutic agents and imaging probes in glioma treatment.
