Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
Department of Radiation Oncology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45219, USA.
Adv Healthc Mater. 2023 Jul;12(19):e2202870. doi: 10.1002/adhm.202202870. Epub 2023 Mar 22.
Targeted radionuclide therapy (TRT) is an emerging therapeutic modality for the treatment of various solid cancers. Current approaches rely on the presence of cancer-specific epitopes and receptors against which a radiolabeled ligand is systemically administered to specifically deliver cytotoxic doses of α and β particles to tumors. In this proof-of-concept study, tumor-colonizing Escherichia coli Nissle 1917 (EcN) is utilized to deliver a bacteria-specific radiopharmaceutical to solid tumors in a cancer-epitope independent manner. In this microbe-based pretargeted approach, the siderophore-mediated metal uptake pathway is leveraged to selectively concentrate copper radioisotopes, Cu and Cu, complexed to yersiniabactin (YbT) in the genetically modified bacteria. Cu-YbT facilitates positron emission tomography (PET) imaging of the intratumoral bacteria, whereas Cu-YbT delivers a cytotoxic dose to the surrounding cancer cells. PET imaging with Cu-YbT reveals persistence and sustained growth of the bioengineered microbes in the tumor microenvironment. Survival studies with Cu-YbT reveals significant attenuation of tumor growth and extends survival of both MC38 and 4T1 tumor-bearing mice harboring the microbes. Tumor response to this pretargeted approach correlates with promising anti-tumor immunity, with noticeable CD8 T:T cell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.
靶向放射性核素治疗 (TRT) 是一种新兴的治疗各种实体瘤的治疗方法。目前的方法依赖于癌症特异性表位和受体的存在，针对这些表位和受体，放射性标记的配体被系统地给予，以将α和β粒子的细胞毒性剂量特异性递送至肿瘤。在这项概念验证研究中，利用肿瘤定植的大肠杆菌 Nissle 1917（EcN）以非癌症表位依赖的方式将细菌特异性放射性药物递送至实体瘤。在这种基于微生物的预靶向方法中，利用铁载体介导的金属摄取途径来选择性地浓缩铜放射性同位素 Cu 和 Cu，其与耶尔森氏菌素（YbT）形成复合物，位于基因修饰的细菌中。Cu-YbT 有助于正电子发射断层扫描（PET）对肿瘤内细菌的成像，而 Cu-YbT 则向周围的癌细胞输送细胞毒性剂量。用 Cu-YbT 进行 PET 成像显示生物工程微生物在肿瘤微环境中的持续存在和持续生长。用 Cu-YbT 进行的生存研究显示，肿瘤生长明显减弱，并且携带微生物的 MC38 和 4T1 荷瘤小鼠的存活时间延长。这种预靶向方法的肿瘤反应与有希望的抗肿瘤免疫相关，具有明显的 CD8 T:T 细胞比值。他们的策略提供了一种针对多种实体瘤的靶向和消融的途径，而不依赖于它们的表位和受体表型。
