An Engineered Probiotic Platform for Cancer Epitope-Independent Targeted Radionuclide Therapy of Solid Tumors.
An Engineered Probiotic Platform for Cancer Epitope-Independent Targeted Radionuclide Therapy of Solid Tumors.
复制标题
用于癌症表位独立的实体瘤靶向放射性核素治疗的工程益生菌平台。
DOI：
10.1002/adhm.202202870
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发表时间：
2023
影响因子：
10
通讯作者：
Kotagiri,Nalinikanth
中科院分区：
文献类型：
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作者：
Siddiqui,NabilA;Ventrola,AlecJ;Hartman,AlexandraR;Konare,Tohonne;Kamble,NitinS;Thomas,ShinduC;Madaan,Tushar;Kharofa,Jordan;Sertorio,MathieuG;Kotagiri,Nalinikanth
靶向放射性核素治疗(TRT)是一种新兴的治疗方法，用于治疗各种实体肿瘤。目前的方法依赖于肿瘤特异性表位和受体的存在，针对这些表位和受体，系统地给药，以特异性地将细胞毒性剂量的α和β颗粒输送到肿瘤。在这项概念验证研究中，肿瘤定植的大肠杆菌1917(ECN)被用来以不依赖于癌症表位的方式将一种细菌特异性的放射性药物输送到实体肿瘤。在这种基于微生物的预靶向方法中，铁载体介导的金属摄取途径被用来选择性地在转基因细菌中浓缩铜放射性同位素64Cu和67Cu，与YbT络合。64Cu-YbT有助于肿瘤内细菌的正电子发射断层扫描(PET)成像，而67Cu-YbT向周围的癌细胞提供细胞毒性剂量。~(64)Cu-YbT的PET成像显示生物工程微生物在肿瘤微环境中持续和持续生长。67Cu-YbT的生存研究显示，肿瘤生长显著减弱，并延长了携带微生物的MC38和4T1荷瘤小鼠的生存时间。肿瘤对这种前靶向途径的反应与有希望的抗肿瘤免疫相关，具有显著的CD8+T/Tregcell比率。他们的策略提供了一种靶向和消融多个实体肿瘤的途径，而不依赖于它们的表位和受体表型。
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 ofαandβparticles to tumors. In this proof‐of‐concept study, tumor‐colonizingEscherichia coliNissle 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,64Cu and67Cu, complexed to yersiniabactin (YbT) in the genetically modified bacteria.64Cu‐YbT facilitates positron emission tomography (PET) imaging of the intratumoral bacteria, whereas67Cu‐YbT delivers a cytotoxic dose to the surrounding cancer cells. PET imaging with64Cu‐YbT reveals persistence and sustained growth of the bioengineered microbes in the tumor microenvironment. Survival studies with67Cu‐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:Tregcell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.