Quantitation of HSV mass distribution in a rodent brain tumor model.
A number of different viral vectors have been used for gene therapy of tumors, with many more under construction, ultimately designed to improve tumor targeting and transduction efficiency. It has become apparent that insufficient viral delivery can be a key limitation to treatment efficacy. We have studied the in vivo mass distribution of a herpes simplex virus type 1 (HSV) vector, hrR3, by radiolabeling it with 111In-oxine. The virus was administered to intracerebral 9L glioma bearing Fisher (F-344) rats by intracarotid and intratumoral injection. The blood half-life of the virus was 1 min (fast component, 10% contribution) and 180 min (slow component, 90% contribution). Approximately 20% of activity had been excreted by 24 h. With intracarotid injection, the total amount of virus that accumulated in tumor was 0.10+/-0.07% of the injected dose (ID)/g at 1 h and 0.19+/-0.01% ID/g at 24 h. By comparison, co-injection of RMP-7, a synthetic bradykinin analog, with the virus, resulted in slightly increased tumor delivery of 0.17+/-0.10% ID/g (P 0.05) at 1 h. The 1 h organ distribution after intra-arterial injection (%ID/organ) was as follows: liver 273+/-2.86%, lung 2.10+/-0.68% and kidney 1.78+/-1.60% with lesser amounts in other organs. When virus was injected directly into the tumor, 71% of virus remained in tumor at 24 h (590+/-212 %ID/g, consistent with the small tumor mass containing most of the virus) with the following distribution regions: tumor > border zone > normal brain (99:40: 1). These studies are the first quantitative mass distribution studies of HSV vectors in an experimental brain tumor model. Localization and quantitation of viral accumulation in vivo will enable detailed analysis of viral and organ interactions critical for advancing the therapeutic use of vectors.
Schellingerhout
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Center for Molecular Imaging Research, Charlestown, MA, USA.
Rainov
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Breakefield
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XO
Weissleder
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R
D000818:Animals; D001921:Brain / Q000821:virology*; D001932:Brain Neoplasms / Q000737:chemistry / Q000628:therapy* / Q000821:virology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000032:analysis*; D049452:Green Fluorescent Proteins; D018259:Herpesvirus 1, Human / Q000235:genetics*; D015552:Injections, Intralesional; D007668:Kidney / Q000821:virology; D008099:Liver / Q000821:virology; D008164:Luminescent Proteins / Q000235:genetics; D008168:Lung / Q000821:virology; D008856:Microscopy, Fluorescence; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000821:virology; D014407:Tumor Cells, Cultured
D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins