Abstract
The ability to monitor the responses of and inhibit the growth of brain tumors during gene therapy has been severely limited due to the blood-brain barrier (BBB). A previous study has demonstrated the feasibility of noninvasive in vivo imaging with 123I-2'-fluoro-2'-deoxy-5-iodo-1-β-D-arabinofuranosyluracil (123I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here, we tested the enhancement of SPECT with 123I-FIAU and ganciclovir (GCV) treatment in brain tumors after BBB disruption induced by focused ultrasound (FUS) in the presence of microbubbles. We established an orthotopic F98 glioma-bearing rat model with trifusion reporter genes. The results of this study showed that the rat model of HSV1-tk-expressing glioma cells could be successfully detected by SPECT imaging after FUS-induced BBB disruption on day 10 after implantation. Compared to the control group, animals receiving the GCV with or without sonication exhibited a significant antitumor activity (P < 0.05) of glioma cells on day 16 after implantation. Moreover, combining sonication with GCV significantly inhibited tumor growth compared with GCV alone. This study demonstrated that FUS may be used to deliver a wide variety of theranostic agents to the brain for molecular imaging and gene therapy in brain diseases.
Highlights
The systemic administration of conventional radiotherapy and chemotherapy can lead to side effects on patients [1, 2]
The main aim of this study was to determine whether the molecular imaging of an established intracranial brain tumor derived from F98/Fluc/GFP/ HSV1-tk (FGT) glioma cells with 123I-FIAU could be enhanced by pulsed focused ultrasound (FUS) exposure
High levels of 123I-FIAU radioactivity accumulation in F98/FGT gliomas with FUS-induced blood-brain barrier (BBB) disruption revealed a high level of herpes simplex virus type 1 thymidine kinase (HSV1-tk) expression (Figure 1A)
Summary
The systemic administration of conventional radiotherapy and chemotherapy can lead to side effects on patients [1, 2]. In contrast with traditional treatments, gene therapy has the potential to be more tumor-specific in terms of targeting and selectively destroying tumor cells by inserting genes conferring drug sensitivity into the tumor cells. Antitumor suicide gene therapy is a new therapeutic strategy for the treatment of patients with otherwise incurable malignant brain tumors. This approach involves the introduction into tumor cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Transfer of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene into tumor cells makes these cells sensitive to antiviral drugs [3]. The HSV1-tk/GCV strategy leads to the death of the transfected tumor cells and of surrounding nontransfected tumor cells [4]
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