Systemic delivery and SPECT/CT in vivo imaging of 125I-labelled oncolytic adenoviral mutants in models of pancreatic cancer

Abstract

Early phase clinical trials have demonstrated good therapeutic index for oncolytic adenoviruses in patients with solid tumours when administered intratumorally, resulting in local tumour elimination. Entrapment and binding of adenovirus to erythrocytes, blood factors, and neutralising antibodies have prevented efficient systemic delivery and targeting of distant lesions in the clinic. We previously generated the novel replication-selective Ad-3∆-A20T to improve tumour targeting by increasing the viral dose at distant sites. Here, we developed a protocol to directly radiolabel the virus for rapid and sensitive detection by single-photon emitted computed tomography (SPECT/CT) providing a convenient method for determining biodistribution following intravenous administration in murine models. Longitudinal whole-body scans, demonstrated efficient viral uptake in pancreatic Suit-2 and Panc04.03 xenografts with trace amounts of 125 I-Ad-3∆-A20T up to 48 h after tail vein delivery. Hepatic and splenic radioactivity decreased over time. Analysis of tissues harvested at the end of the study, confirmed potency and selectivity of mutant viruses. Ad-3∆-A20T-treated animals showed higher viral genome copy numbers and E1A gene expression in tumors than in liver and spleen compared to Ad5wt. Our direct radiolabeling approach, allows for immediate screening of novel oncolytic adenoviruses and selection of optimal viral genome alterations to generate improved mutants.

Development of a low-seroprevalence, αvβ6 integrin-selective virotherapy based on human adenovirus type 10

“…To provide a high-affinity, tumor-selective means of infection, we incorporated A20 peptide, as previously described. 26 , 32 , 33 , 34 , 35 A20 has high selectivity and affinity for αvβ6 integrin, which is absent on normal epithelial cells but overexpressed on aggressively transformed epithelial cells, in particular malignancies of pancreatic, breast, esophageal, and ovarian origins. 37 , 38 , 39 , 40 , 41 We inserted A20 into the DG loop of HAdV-D10 fiber knob.…”

“…The resulting basal Ad5 NULL vector was targeted to αvβ6 integrin through insertion of a 20-amino acid peptide, NAVPNLRGDLQVLAQKVART (A20), native to foot and mouth disease virus (FMDV). 31 A20-modified viruses 32 , 33 , 34 , 35 selectively infect cells expressing αvβ6 integrin, a surface protein upregulated in several epithelial carcinomas, 36 including breast, ovarian, pancreatic, and colorectal. 37 , 38 , 39 Targeting αvβ6 integrin is advantageous in the context of cancer therapies, as it drives metastasis and tumor invasion through TGF-β activation and is consequently associated with poor prognosis.…”

Harnessing the power of foot-and-mouth-disease virus for targeting integrin alpha-v beta-6 for the therapy of cancer

“…Furthermore, using pancreatic cancer xenografts in mice, tumor progression was significantly reduced using either adenoviral treatments, from 11 days in the untreated animals to a median of 42 days in the animals treated with Ad5-3Δ-A20T. Ad5-3Δ-A20T was subsequently radiolabelled with Iodine-125 to determine the biodistribution of the virus [50]. They demonstrated that uptake of the virus was rapid, with Ad5-3Δ-A20T replication in tumor cells significantly higher than the wild-type virus 48 hours post-administration in tumor cells.…”

Cell-Based Tracers as Trojan Horses for Image-Guided Surgery

“…The fact that they performed the dye-coupling reaction at room temperature for only 1 hour suggests that their approach would be feasible in a clinical setting. In the context of SPECT-CT, it was shown by Stella Man et al that systemically administered Iodine-125-labeled oncolytic adenoviral mutants could be monitored in real time using murine pancreatic cancer models [ 149 ]. The researchers designed a radiolabeling procedure with optimized conditions, retaining the adenoviral tumor-targeting functions.…”