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Abstract
Bacteria-mediated cancer-targeted therapy is a novel experimental strategy for the treatment of cancers. Bacteria can be engineered to overcome a major challenge of existing therapeutics by differentiating between malignant and healthy tissue. A prerequisite for further development and study of engineered bacteria is a suitable imaging concept which allows bacterial visualization in tissue and monitoring bacterial targeting and proliferation. Optoacoustics (OA) is an evolving technology allowing whole-tumor imaging and thereby direct observation of bacterial colonization in tumor regions. However, bacterial detection using OA is currently hampered by the lack of endogenous contrast or suitable transgene fluorescent labels. Here, we demonstrate improved visualization of cancer-targeting bacteria using OA imaging and E. coli engineered to express tyrosinase, which uses L-tyrosine as the substrate to produce the strong optoacoustic probe melanin in the tumor microenvironment. Tumors of animals injected with tyrosinase-expressing E. coli showed strong melanin signals, allowing to resolve bacterial growth in the tumor over time using multispectral OA tomography (MSOT). MSOT imaging of melanin accumulation in tumors was confirmed by melanin and E. coli staining. Our results demonstrate that using tyrosinase-expressing E. coli enables non-invasive, longitudinal monitoring of bacterial targeting and proliferation in cancer using MSOT.

Affiliations

Misun Yun 1, Sung-Hwan You 2, Vu Hong Nguyen 3, Jaya Prakash 1 4, Sarah Glasl 1, Vipul Gujrati 1 5, Hyon E Choy 6, Andre C Stiel 1, Jung-Joon Min 7, Vasilis Ntziachristos 8 9
1Institute of Biological and Medical Imaging, Helmholtz Zentrum München GmbH, 85764, Neuherberg, Germany.
2Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
3Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
4Department of Instrumentation and Applied Physics, Indian Institute of Science, C. V. Raman Avenue, Bengaluru, 560 012, India.
5Chair of Biological Imaging at the Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675, Munich, Germany.
6Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
7Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea. jjmin@jnu.ac.kr.
8Institute of Biological and Medical Imaging, Helmholtz Zentrum München GmbH, 85764, Neuherberg, Germany. bioimaging.translatum@tum.de.
9Chair of Biological Imaging at the Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675, Munich, Germany. bioimaging.translatum@tum.de.