Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy.
Microglia are phagocytic cells that are chemoattracted by brain tumors and can represent up to 70% of the tumor cell population. To get insight into gene therapy against glioma, we decided to take advantage of those microglia properties and to use those cells as vehicles to transport simultaneously a suicide gene (under the control of a heat-sensitive promoter) and contrast agents to localize them by magnetic resonance imaging before applying any therapeutic treatment. Thymidine kinase (TK) expression and its functionality after gancyclovir administration were investigated. After the heat shock (44 degrees C and 20 min), TK was expressed in 50% of the cells. However, after gancyclovir treatment, 90% of the cells died by apoptosis, showing an important bystander effect. Then, the cells were incubated with new lanthanide contrast agents to check both their potential toxicity and their MR properties. Results indicate that the nanoparticles did not induce any cell toxicity and yield a hypersignal on MR images at 4.7 T. These in vitro experiments indicate that microglia are good candidates as vectors in gene therapy against brain tumors. Finally, microglia containing gadolinium-grafted nanoparticles were injected in the close vicinity of C6 tumor, in a mouse. The hyperintensive signal obtained on in vivo images as well as its retention time show the potential of the novel contrast agents for cellular imaging.
Ribot
E
E
Centre de Résonance Magnétique des Systèmes Biologiques, UMR 5536, CNRS-Université V. Segalen, Bordeaux, France. ribot@rmsb.u-bordeaux2.fr
Bouzier-Sore
A-K
AK
Bouchaud
V
V
Miraux
S
S
Delville
M-H
MH
Franconi
J-M
JM
Voisin
P
P
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003287:Contrast Media; D005260:Female; D017930:Genes, Reporter; D015316:Genetic Therapy; D005910:Glioma / Q000628:therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D017628:Microglia / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*
D003287:Contrast Media; D013937:Thymidine Kinase