Focused ultrasound enhanced molecular imaging and gene therapy for multifusion reporter gene in glioma-bearing rat model.
Authors: Yang FY, Chang WY, Lin WT, Hwang JJ, Chien YC, Wang HE, Tsai ML
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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To test whether focused ultrasound-induced blood–brain barrier disruption enhances SPECT imaging with 123I-FIAU and ganciclovir-mediated therapy of HSV1-tk-expressing gliomas in a rat model.
Animal model / Human subject
Rat (orthotopic F98 glioma-bearing model); strain: not specified; age: 11-13 weeks; sex: male
Disease model
glioma
Targeted brain region(s)
Hemisphere Tumor Site
Target coordinates
5 mm posterior and 3 mm lateral to bregma; 5 mm depth from the brain surface
Cargo name and characteristics
HSV1-tk transgene (viral thymidine kinase enzyme expressed as part of trifusion reporter genes; gene/protein), 123I-FIAU (iodinated radiolabeled nucleoside analog SPECT tracer; small molecule radiotracer), Ganciclovir (GCV) (antiviral/nucleoside analog prodrug activated by HSV1-tk; small molecule)
Route of administration
123I-FIAU: Intravenous; Ganciclovir: Intraperitoneal
Outcomes and Safety
Summary of Outcomes
Pulsed focused ultrasound (FUS)-induced BBB disruption (with microbubbles and sonication performed before GCV on days 11, 14, and 17) significantly increased delivery and SPECT detection of 123I-FIAU to HSV1-tk–expressing F98 gliomas and enhanced ganciclovir (GCV) antitumor efficacy, producing greater tumor growth inhibition than GCV alone.
Safety-related matter
No adverse effects were reported in this study; the authors note that FUS may help ameliorate GCV’s cytotoxic side effects by enabling a reduction in systemic GCV dose.
Brain Region
Ultrasound Parameters
Ultrasound instrument
1.0 MHz, single-element focused transducer (A392S, Panametrics, Waltham, MA, USA)
FUS Frequency
1.0 MHz
FUS Pressure
0.7 Mpa (peak negative pressure)
FUS Mode
pulsed
Pulse duration
50 ms
Duration of a single FUS session
60 s
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
multiple
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