SonoBacter: Ultrasound-guided Activation and Imaging of Engineered Bacteria for Stroma Reprogramming

SonoBacter：用于基质重编程的工程细菌的超声引导激活和成像

• 批准号: MR/Y008227/1
• 负责人: Ljiljana Fruk
• 金额: $ 6.67万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY008227%2F1
• 关键词: SonoBacter; Ultrasound; guided; Activation; Imaging

Bacteria have been investigated for cancer therapies, either for their abilities to produce drug molecules or enzymes that can attack tumours, or to induce immune responses that could help remove cancer cells. There are a number of issues with the use of existing bacteria-mediated cancer therapies, primarily concerning their mode of action and the danger that insufficient number of bacteria will be retain in cancer tissue and that they enter the blood system to cause infection. Our proposal addresses these issues by focusing on reprogramming the tumour environment rather than killing cancer cells, including a means to retain the bacteria where they are injected, and providing their on-demand activation. This approach supports the innate mechanisms of cancer removal, does not lead to drug resistance and uses nature-inspired compounds that can impact the metabolism of non-cancerous cells within solid tumours rather than employing highly toxic traditional cancer drugs. The bacteria in our study will be engineered to carry genes which can be activated by a simple chemical signal to produce plant-based compounds, known as flavonoids, that have effects on non-cancerous cells. The chemical signal molecule will be packaged within small particles encased within a material that forms a gel upon injection into the body. This gel also encapsulates the bacteria and ensures their safe delivery and retention at the injection site. When ultrasound is applied to the capsule, the particles will burst and release the signal molecule, which in turn activates the bacteria and initiates the production of flavonoids. In this way, release of the active cargoes is controlled externally and can be initiated on-demand, thus ensuring the correct location of delivery and the desired in-tumour concentration of flavonoid compounds. In addition to bacterial activation, ultrasound can also be used for imaging, with the help of contrast agent programmed into the bacteria, allowing us to monitor non-invasively the mobility of the bacteria in the gel and their growth into and within the tumour. Furthermore, the gel material can be easily modified so that it is suitable either for injection via endoscopic needle or post-surgery insertion into the tumour, making it rapidly applicable to current medical practice. The culmination of the study will be evaluation of bacterial anti-cancer activity in advanced 3D models of pancreatic and lung cancer, which will enable optimisation of bacterial population, active compound release and activity assessment without animal use.

细菌已经被研究用于癌症治疗，无论是因为它们能够产生可以攻击肿瘤的药物分子或酶，还是因为它们能够诱导有助于清除癌细胞的免疫反应。使用现有的细菌介导的癌症疗法存在许多问题，主要涉及它们的作用模式以及在癌组织中保留的细菌数量不足以及它们进入血液系统引起感染的危险。我们的提案通过专注于重新编程肿瘤环境而不是杀死癌细胞来解决这些问题，包括保留细菌的方法，并提供它们的按需激活。这种方法支持癌症去除的先天机制，不会导致耐药性，并使用自然启发的化合物，可以影响实体瘤内非癌细胞的代谢，而不是使用高毒性的传统癌症药物。我们研究中的细菌将被改造为携带基因，这些基因可以被一个简单的化学信号激活，产生植物基化合物，称为黄酮类化合物，对非癌细胞有影响。化学信号分子将被包装在一种材料内的小颗粒中，该材料在注射到体内时形成凝胶。这种凝胶还封装了细菌，并确保其安全输送和保留在注射部位。当对胶囊施加超声波时，颗粒会破裂并释放信号分子，从而激活细菌并启动类黄酮的产生。以这种方式，活性货物的释放是外部控制的，并且可以按需启动，从而确保正确的递送位置和所需的类黄酮化合物的肿瘤内浓度。除了细菌激活之外，超声还可以用于成像，在造影剂编程到细菌中的帮助下，使我们能够非侵入性地监测凝胶中细菌的流动性及其在肿瘤中的生长。此外，凝胶材料可以容易地改性，使得其适合于通过内窥镜针注射或手术后插入肿瘤中，使其快速适用于当前的医疗实践。该研究的最终结果将是在胰腺癌和肺癌的高级3D模型中评估细菌抗癌活性，这将能够在不使用动物的情况下优化细菌种群、活性化合物释放和活性评估。