Combining the specificity of tumor‐targeting bacteria with the sensitivity of biomarker detection would create a screening method able to detect small tumors and metastases. To create this system, we genetically modified an attenuated strain of
Tumor heterogeneity makes cancer difficult to treat. Many small molecule cancer drugs target rapidly dividing cells on the periphery of tumors but have difficulty in penetrating deep into tumors and are ineffective at treating entire tumors. Targeting both rapidly dividing and slower growing regions of tumors is essential to effectively treat cancer. A cancer drug carrier that penetrates deep into tumors and identifies metabolically activity could supply treatment to those areas based on the local microenvironment. We hypothesized that glucose sensing bacteria could identify sugar gradients in solid tumors. To test this hypothesis, a genetic circuit was designed to trigger expression of a green fluorescent protein (GFP) reporter through the chemotaxis‐osmoporin fusion protein, Trz1, a receptor for sensing glucose and ribose sugars.
- NSF-PAR ID:
- 10236780
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Biotechnology and Bioengineering
- Volume:
- 113
- Issue:
- 11
- ISSN:
- 0006-3592
- Page Range / eLocation ID:
- p. 2474-2484
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Salmonella enterica to release a recombinant fluorescent biomarker (or fluoromarker).Salmonella expressing ZsGreen were intravenously administered to tumor‐bearing mice and fluoromarker production was induced after 48 hr. The quantities and locations of bacteria and ZsGreen were measured in tumors, livers and spleens by immunofluorescence, and the plasma concentration of ZsGreen was measured using single‐layer ELISA. In the plasma, the ZsGreen concentration was in the range of 0.5–1.5 ng/ml and was dependent on tumor mass (with a proportion of 0.81 ± 0.32 ng·ml−1·g−1). No adverse reaction to ZsGreen or bacteria was observed in any mice. ZsGreen was released at an average rate of 4.3 fg·CFU−1·hr−1and cleared from the plasma with a rate constant of 0.259 hr−1. ZsGreen production was highest in viable tissue (7.6 fg·CFU−1·hr−1) and lowest in necrotic tissue (0.47 fg·CFU−1·hr−1). The mass transfer rate constant from tumor to blood was 0.0125 hr−1. Based on these measurements, this system has the capability to detect tumors as small as 0.12 g. These results demonstrate four essential mechanisms of this method: (i ) preferential tumor colonization by bacteria, (ii ) fluoromarker releasein vivo , (iii ) fluoromarker transport through tumor tissue and (iv ) slow enough systemic clearance to enable measurement. This bacteria‐based blood test would be minimally invasive and has the potential to identify previously undetectable microscopic tumors. -
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