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. 2012;7(3):e32871.
doi: 10.1371/journal.pone.0032871. Epub 2012 Mar 7.

SPECT/CT imaging of hNIS-expression after intravenous delivery of an oncolytic adenovirus and 131I

Maria Rajecki  1 , Mirkka Sarparanta, Tanja Hakkarainen, Mikko Tenhunen, Iulia Diaconu, Venla Kuhmonen, Kalevi Kairemo, Anna Kanerva, Anu J Airaksinen, Akseli Hemminki
Affiliations

SPECT/CT imaging of hNIS-expression after intravenous delivery of an oncolytic adenovirus and 131I

Maria Rajecki et al. PLoS One. 2012.

Abstract

Oncolytic adenoviruses can be engineered for better tumor selectivity, gene delivery and be armed for imaging and concentrating radionuclides into tumors for synergistic oncolysis. We constructed Ad5/3-hTERT-hNIS where replication is controlled by hTERT-promoter. Ad5/3-hTERT-hNIS expresses hNIS for imaging of transgene expression and for treatment of infected tumors by radioiodine. Ad5/3-hTERT-hNIS efficiently killed prostate cancer cells and induced iodine uptake in vitro and in vivo after intratumoral virus administration. Survival of mice treated with intravenous Ad5/3-hTERT-hNIS significantly prolonged survival over mock or radioiodine only but the combination of virus with radioiodine was not more effective than virus alone. Temporal and spatial changes in hNIS-expression during therapy were detected with SPECT, demonstrating feasibility of evaluation of the combination therapy with hNIS-expressing adenoviruses and radioiodide.

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Conflict of interest statement

Competing Interests: A. Hemminki is a co-founder and shareholder in Oncos Therapeutics ltd. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Figure 1
Figure 1. hNIS-expression in prostate cancer cells.
(a) Cells were infected with 10 vp of Ad5/3-hTERT-hNIS (lanes 1 and 3) or control virus Ad5/3-hTERT-Δgp19K (lanes 2 and 4). hNIS-RNA -expression was assayed 24 h (lanes 1 and 2) and 48 h (lanes 3 and 4) later by RT-PCR. ß-actin served as an internal control. (b) 125I uptake in prostate cancer cells infected in triplicates with 10 vp of Ad5/3-hTERT-hNIS or Ad5/3-hTERT-Δgp19K. The capability of the cells to concentrate iodide was assessed at 24 h and 48 h after infection. Student's t-test was used for statistical analyses, *p<0.05, **p<0.01, ***p<0.001 as compared to uninfected cells. Bars represent SD.
Figure 2
Figure 2. Oncolytic potency of Ad5/3-hTERT-hNIS.
Prostate cancer cells were infected in triplicates with 0.01 to 100 vp/cell and the cell viability was assessed by MTS-assay. Ad5/3Luc1 is a replication-deficient adenovirus. Ad5 WT is the serotype 5 wild-type adenovirus. Ad5/3-hTERT-Δgp19K is similar to Ad5/3-hTERT-hNIS but does not contain hNIS. ***p<0.001 as compared to replication-deficient adenovirus. Bars represent SD.
Figure 3
Figure 3. In vivo iodide uptake and efficacy.
(a) Tumor uptake of 123I− 0.5 h, 2 h and 13 h after i.v. administration of 123I−. The tumors were injected twice with hTERT-viruses 24 h and 48 h prior to radioiodide. 1, Mock-injected tumor; 2, Ad5/3-hTERT-Δgp19K-injected tumor; 3 and 4, Ad5/3-hTERT-hNIS-injected tumors. (b) Ad5/3-hTERT-hNIS significantly prolongs the survival of mice bearing intra pulmonary PC-3MM2 tumors. Mice received 5×1010 vp of Ad5/3-hTERT-hNIS or diluent intravenously. Next day, the mice were injected intraperitoneally with 131I−. The treatments were repeated once a week for a total of three weeks. Pairwise comparisons with the logrank test were used to compare survival curves, **p<0.01, ***p<0.001 as compared to mock-treated mice. (c) Biodistribution of 131I− in mice 48 h after the first intravenous Ad5/3-hTERT-hNIS-injection and 24 h after first radioiodide-injection. Bars represent SD.
Figure 4
Figure 4. SPECT/CT is sensitive for detecting endogenous NIS- and hNIS-expression.
Mice were given Ad5/3-hTERT-hNIS or diluent and 123I− intravenously for SPECT-scanning. After the SPECT/CT-scan, mice received 131I− or PBS intraperitoneally. The iodide uptakes were calculated weekly and normalized to the injected dose of 123I−. (a) Individual tumor uptake of 123I− (the imaging isotope) in Ad5/3-hTERT-hNIS and Ad5/3-hTERT-hNIS+131I− -treated mice. All mice received 123I− for evaluation of iodide uptake by SPECT. Mice in the latter group also received 131I− right after the SPECT imaging for therapeutic purposes. Solid grey line, background level in the absence of Ad5/3-hTERT-hNIS; dotted grey lines, ± SD of background. (b) 123I− uptake in the thyroids. Results are expressed as %ID/mm3×1000 ± SD.
Figure 5
Figure 5. Increasing amount of 123I− accumulates in the tumor over time showing progressive virus replication and increasing tumor hNIS-expression.
(a) SPECT/CT image (sagittal section) showing 123I− accumulation into tumor in the lungs of a mouse treated intravenously with Ad5/3-hTERT-hNIS and intraperitoneally with 131I−. (b) Control mouse treated with 131I− only shows no 123I− -accumulation in the lungs on the course of the treatment. (c) Transverse section of the lungs of the mouse shown in (a) shows accumulation of 123I− into the tumor on the third treatment week. (d) Transverse section of lungs of the mouse shown in (b) shows no accumulation of 123I− into the tumor on the third treatment week. The crossing point of red lines indicates tumor localization.
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