Institute of Biological and Medical Imaging, Helmholtz Zentrum München GmbH, 85764, Neuherberg, Germany.
Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
Sci Rep. 2021 Dec 24;11(1):24430. doi: 10.1038/s41598-021-04047-4.
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.
细菌介导的癌症靶向治疗是一种治疗癌症的新型实验策略。细菌可以被设计为通过区分恶性和健康组织来克服现有治疗方法的一个主要挑战。进一步开发和研究工程细菌的前提是要有一个合适的成像概念，该概念允许在组织中可视化细菌，并监测细菌的靶向和增殖。光声（OA）是一种不断发展的技术，允许对整个肿瘤进行成像，从而可以直接观察肿瘤区域中细菌的定植。然而，由于缺乏内源性对比或合适的转基因荧光标记物，目前 OA 用于细菌检测受到限制。在这里，我们通过表达酪氨酸酶的大肠杆菌的光声成像来证明对癌症靶向细菌的可视化得到了改善，该细菌利用 L-酪氨酸作为底物在肿瘤微环境中产生强光声探针黑色素。用表达酪氨酸酶的大肠杆菌注射的动物肿瘤显示出强烈的黑色素信号，从而可以使用多光谱光声断层扫描（MSOT）随时间分辨肿瘤中的细菌生长。通过黑色素和大肠杆菌染色证实了 MSOT 对肿瘤中黑色素积累的成像。我们的研究结果表明，使用表达酪氨酸酶的大肠杆菌可以通过 MSOT 实现对癌症中细菌靶向和增殖的非侵入性、纵向监测。
