Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir

Win Ping Deng, Wen K. Yang, Wen-FuThomas Lai, Ren Shyan Liu, Jeng Jong Hwang, Den Mei Yang, Ying Kai Fu, Hsin Ell Wang

研究成果: 雜誌貢獻文章

35 引文 (Scopus)

摘要

An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2′-fluoro-2′ -deoxy-5-iodo-1-β-D-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give "hot kits". The labelling yield was over 95%, with a radiochemical purity of more than 98%. The stability of [131I]FIAU in the form of lyophilised powder (the hot kit) was much better than that in the normal saline solution. The shelf life of the final [131I]FIAU hot kit product is as long as 4 weeks. Cellular uptake of [131I]FIAU after different periods of storage was investigated in vitro with HSV1-tk-retroviral vector transduced NG4TL4-STK and parental non-transduced NG4TL4 murine sarcoma cell lines over an 8-h incubation period. The NG4TL4-STK cells accumulated more radioactivity than NG4TL4 cells in all conditions, and accumulation increased with time up to 8 h. The kinetic profile of the cellular uptake of n.c.a. [131]FIAU formulated from the lyophilised hot kit or from the stock solution was qualitatively similar. For animal model cancer gene therapy studies, FVB/N mice were inoculated subcutaneously with the HSV1-tk(+) and tk(-) sarcoma cells into the flank to produce tumours. Biodistribution studies showed that tumour/blood ratios were 2, 3.5, 8.2 and 386.8 at 1, 4, 8 and 24 h post injection, respectively, for the HSV1-tk(+) tumours, and 0.5, 0.5, 0.7 and 5.4, respectively, for the HSV1-tk(-) tumours. Radiotracer clearance from blood was completed in 24 h and was bi-exponential. A significant difference in radioactivity accumulation was revealed among the HSV1-tk(+) tumours, the tk(-) tumours and other tissues. At 24 h p.i., higher activity retention was observed in HSV1-tk(+) tumours (9.67%±3.89%ID/g) than in HSV1-tk(-) tumours (0.48%±0.19%ID/g). After seven consecutive daily treatments with the prodrug ganciclovir, planar gamma camera imaging showed HSV1-tk(+) tumour regression at day 4, and complete tumour regression at day 7. These results clearly demonstrate that the simplified n.c.a. synthesis process developed in this study is reliable and that the [131I]FIAU product is useful for in vivo monitoring of HSV1-tk gene transfer, expression and gene therapy.
原文英語
頁(從 - 到)99-109
頁數11
期刊European Journal of Nuclear Medicine and Molecular Imaging
31
發行號1
DOIs
出版狀態已發佈 - 一月 2004

指紋

Ganciclovir
Thymidine Kinase
Neoplasm Genes
Human Herpesvirus 1
Genetic Therapy
Neoplasms
Genes
Sarcoma
Radioactivity
Arabinofuranosyluracil
fialuridine
Gene Expression
Prodrugs
Transgenes
Sodium Chloride
Radionuclide Imaging
Iodine
Powders
Animal Models
Cell Line

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

引用此文

Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir. / Deng, Win Ping; Yang, Wen K.; Lai, Wen-FuThomas; Liu, Ren Shyan; Hwang, Jeng Jong; Yang, Den Mei; Fu, Ying Kai; Wang, Hsin Ell.

於: European Journal of Nuclear Medicine and Molecular Imaging, 卷 31, 編號 1, 01.2004, p. 99-109.

研究成果: 雜誌貢獻文章

Deng, Win Ping ; Yang, Wen K. ; Lai, Wen-FuThomas ; Liu, Ren Shyan ; Hwang, Jeng Jong ; Yang, Den Mei ; Fu, Ying Kai ; Wang, Hsin Ell. / Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir. 於: European Journal of Nuclear Medicine and Molecular Imaging. 2004 ; 卷 31, 編號 1. 頁 99-109.
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abstract = "An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2′-fluoro-2′ -deoxy-5-iodo-1-β-D-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give {"}hot kits{"}. The labelling yield was over 95{\%}, with a radiochemical purity of more than 98{\%}. The stability of [131I]FIAU in the form of lyophilised powder (the hot kit) was much better than that in the normal saline solution. The shelf life of the final [131I]FIAU hot kit product is as long as 4 weeks. Cellular uptake of [131I]FIAU after different periods of storage was investigated in vitro with HSV1-tk-retroviral vector transduced NG4TL4-STK and parental non-transduced NG4TL4 murine sarcoma cell lines over an 8-h incubation period. The NG4TL4-STK cells accumulated more radioactivity than NG4TL4 cells in all conditions, and accumulation increased with time up to 8 h. The kinetic profile of the cellular uptake of n.c.a. [131]FIAU formulated from the lyophilised hot kit or from the stock solution was qualitatively similar. For animal model cancer gene therapy studies, FVB/N mice were inoculated subcutaneously with the HSV1-tk(+) and tk(-) sarcoma cells into the flank to produce tumours. Biodistribution studies showed that tumour/blood ratios were 2, 3.5, 8.2 and 386.8 at 1, 4, 8 and 24 h post injection, respectively, for the HSV1-tk(+) tumours, and 0.5, 0.5, 0.7 and 5.4, respectively, for the HSV1-tk(-) tumours. Radiotracer clearance from blood was completed in 24 h and was bi-exponential. A significant difference in radioactivity accumulation was revealed among the HSV1-tk(+) tumours, the tk(-) tumours and other tissues. At 24 h p.i., higher activity retention was observed in HSV1-tk(+) tumours (9.67{\%}±3.89{\%}ID/g) than in HSV1-tk(-) tumours (0.48{\%}±0.19{\%}ID/g). After seven consecutive daily treatments with the prodrug ganciclovir, planar gamma camera imaging showed HSV1-tk(+) tumour regression at day 4, and complete tumour regression at day 7. These results clearly demonstrate that the simplified n.c.a. synthesis process developed in this study is reliable and that the [131I]FIAU product is useful for in vivo monitoring of HSV1-tk gene transfer, expression and gene therapy.",
keywords = "[I]FIAU, Ganciclovir, Gene therapy, Herpes simplex virus, Non-invasive imaging, Thymidine kinase",
author = "Deng, {Win Ping} and Yang, {Wen K.} and Wen-FuThomas Lai and Liu, {Ren Shyan} and Hwang, {Jeng Jong} and Yang, {Den Mei} and Fu, {Ying Kai} and Wang, {Hsin Ell}",
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doi = "10.1007/s00259-003-1269-z",
language = "English",
volume = "31",
pages = "99--109",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",
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T1 - Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir

AU - Deng, Win Ping

AU - Yang, Wen K.

AU - Lai, Wen-FuThomas

AU - Liu, Ren Shyan

AU - Hwang, Jeng Jong

AU - Yang, Den Mei

AU - Fu, Ying Kai

AU - Wang, Hsin Ell

PY - 2004/1

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N2 - An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2′-fluoro-2′ -deoxy-5-iodo-1-β-D-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give "hot kits". The labelling yield was over 95%, with a radiochemical purity of more than 98%. The stability of [131I]FIAU in the form of lyophilised powder (the hot kit) was much better than that in the normal saline solution. The shelf life of the final [131I]FIAU hot kit product is as long as 4 weeks. Cellular uptake of [131I]FIAU after different periods of storage was investigated in vitro with HSV1-tk-retroviral vector transduced NG4TL4-STK and parental non-transduced NG4TL4 murine sarcoma cell lines over an 8-h incubation period. The NG4TL4-STK cells accumulated more radioactivity than NG4TL4 cells in all conditions, and accumulation increased with time up to 8 h. The kinetic profile of the cellular uptake of n.c.a. [131]FIAU formulated from the lyophilised hot kit or from the stock solution was qualitatively similar. For animal model cancer gene therapy studies, FVB/N mice were inoculated subcutaneously with the HSV1-tk(+) and tk(-) sarcoma cells into the flank to produce tumours. Biodistribution studies showed that tumour/blood ratios were 2, 3.5, 8.2 and 386.8 at 1, 4, 8 and 24 h post injection, respectively, for the HSV1-tk(+) tumours, and 0.5, 0.5, 0.7 and 5.4, respectively, for the HSV1-tk(-) tumours. Radiotracer clearance from blood was completed in 24 h and was bi-exponential. A significant difference in radioactivity accumulation was revealed among the HSV1-tk(+) tumours, the tk(-) tumours and other tissues. At 24 h p.i., higher activity retention was observed in HSV1-tk(+) tumours (9.67%±3.89%ID/g) than in HSV1-tk(-) tumours (0.48%±0.19%ID/g). After seven consecutive daily treatments with the prodrug ganciclovir, planar gamma camera imaging showed HSV1-tk(+) tumour regression at day 4, and complete tumour regression at day 7. These results clearly demonstrate that the simplified n.c.a. synthesis process developed in this study is reliable and that the [131I]FIAU product is useful for in vivo monitoring of HSV1-tk gene transfer, expression and gene therapy.

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KW - [I]FIAU

KW - Ganciclovir

KW - Gene therapy

KW - Herpes simplex virus

KW - Non-invasive imaging

KW - Thymidine kinase

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