A Molecular Imaging System Based on Both Transcriptional and Genomic Amplification to Detect Prostate Cancer Cells In Vivo

Abstract

An imaging modality that can accurately discern prostate cancer (PCa) foci would be useful to detect PCa early or guide treatment. We have engineered numerous adenoviral vectors (Ads) to carry out reporter gene-based imaging using specific promoters to express a potent transcriptional activator, which in turn activates the reporter gene in PCa. This two-step transcriptional amplification (TSTA) method can boost promoters' activity, while maintaining cell specificity. Here, we examined a dual TSTA (DTSTA) approach, which utilizes TSTA not only to express the imaging reporter, but also to direct viral genome replication of a conditionally replicating Ad (CRAd) to further augment the expression levels of the reporter gene by genomic amplification supported in trans by coadministered CRAd. In vitro studies showed up to 50-fold increase of the reporter genome by DTSTA. Compared with TSTA reporter alone, DTSTA application exhibited a 25-fold increase in imaging signal in PCa xenografts. DTSTA approach is also beneficial for a combination of two TSTA Ads with distinct promoters, although amplification is observed only when TSTA-CRAd can replicate. Consequently, the DTSTA approach is a hybrid method of transcriptional and genomic augmentation that can provide higher level reporter gene expression potentially with a lower dose of viral administration.