A 3-D whole body imaging technique applied to visualize bacterial trafficking in tumor-bearing mice has demonstrated the potential for harnessing nonpathogenic bacteria as vectors for the targeted delivery of cancer therapies. Researchers at University College Cork, Ireland, and colleagues, used 3-dimensional bioluminescent imaging (BLI) combined with micro-computed tomography (μCT), to track harmless lux-expressing commensal bacteria including E. coli K-12 MG1655 and Bifidobacterium breve UCC2003, administered intravenously to mice bearing subcutaneous Fluc-expressing xenograft tumors. Mark Tangney, M.D., and colleagues describe their approach and results in PLoS One in a paper titled “High Resolution In Vivo Bioluminescent Imaging for the Study of Bacterial Tumour Targeting.”
BLI traditionally used as a 2-D modality provides no depth of information, whereas the 3-D imaging approach reported by the Cork team is capable of revealing the precise location of lux-expressing bacteria within tumors, and also enables visualization of tumor vasculature when a contrast agent was used.
For example, their studies of bacterial trafficking and tumor targeting in mice showed that while 2-D imaging data could only show that B. breve bacteria were distributed throughout the tumor, combining 3-D BLI with μCT analysis to interpret the images revealed that there was in fact a pattern of multiple, nonuniform clusters of bacteria within tumors. This was confirmed by histological analysis, which demonstrated the presence of B. breve in clusters, sited particularly in the less viable, hypoxic regions of the tumor mass.
Importantly, as well as demonstrating the utility of the imaging approach to precisely track bacterial trafficking in vivo, the research also verifies the potential to use nonpathogenic bacteria for the potential delivery of agents to tumor sites, the authors state. Preclinical work to date has focused largely on engineered pathogenic strains, and in particular Salmonella typhimurium.
The researchers note that in the context of gene and cell therapy, nonpathogenic bacteria vectors would act not as transfection agents, but instead replicate within the tumor stroma, external to tumor cells. This therapeutic strategy is more akin to cell therapy approaches, as the bacterial expression of therapeutic genes such as, for example, anti-angiogenic or immune modulating factors, would occur within the environment of the tumor, rather than within the tumor cells.
“Overall, we demonstrate the potential for nonpathogenic bacteria as vectors for cancer therapy,” Dr. Tangney et al conclude. “Analysis of reporter gene activity from these strains not only demonstrates their potential as safe and noninvasive vectors, with the potential to deliver therapeutic or diagnostic agents systemically, but furthermore underlines the significance of BLI and μCT co-registration as tools to advance this concept.”