RESUMO
For the past two decades, the emerging role of the endothelin (ET) axis in cancer has been extensively investigated, and its involvement in several mechanisms described as "hallmarks of cancer" has clearly highlighted its potential as a therapeutic target. Despite the growing interest in finding effective anticancer drugs, no breakthrough treatment has successfully made its way to the market. Recently, our team reported the development of a new immuno-positron emission tomography probe targeting the ET A receptor (ETA, one of the ET receptors) that allows the successful detection of ETA+ glioblastoma, paving the way for the elaboration of novel antibody-based strategies. In this study, we describe the synthesis of two PET/NIRF (positron emission tomography/near-infrared fluorescence) dually functionalized imaging agents, directed against ETA or ETB, that could be used to detect ET+ tumors and select patients that will be eligible for fluorescence-guided surgery. Both imaging modalities were brought together using a highly versatile tetrazine platform bearing the IRDye800CW fluorophore and desferrioxamine for 89Zr chelation. This so-called monomolecular multimodal imaging probe was then "clicked", via an inverse-electron-demand Diels-Alder reaction, to antibodies conjugated site-specifically with a trans-cyclooctene group. This approach has led to homogeneous and well-defined constructs that retained their high affinity and high specificity for their respective target, as shown by flow cytometry and NIRF in vivo imaging experiments in nude mice bearing CHO-ETA and CHO-ETB tumors. Ultimately, these bimodal immunoconjugates could be used to improve the outcomes of patients with ET+ tumors.
Assuntos
Glioblastoma , Imunoconjugados , Animais , Camundongos , Humanos , Receptores de Endotelina , Camundongos Nus , Tomografia por Emissão de Pósitrons/métodos , Imagem Óptica/métodos , Linhagem Celular TumoralRESUMO
Neurotensin receptor 1 (NTSR1) is overexpressed in most human pancreatic ductal adenocarcinomas. It makes it an attractive target for the development of pancreatic cancer imaging agents. In this study, we sought to develop a bimodal positron emission tomography (PET)/fluorescent imaging agent capable of specifically targeting these receptors. Starting from the structure of a known NTSR1 agonist, a series of tracers were synthesized, radiometalated with gallium-68, and evaluated in vitro and in vivo, in mice bearing an AsPC-1 xenograft. PET imaging allowed us to identify the compound [68Ga]Ga-NODAGA-Lys(Cy5**)-AEEAc-[Me-Arg8,Tle12]-NT(7-13) as the one with the most promising biodistribution profile, characterized by high tumor uptake (2.56 ± 0.97%ID/g, 1 h post-injection) and rapid elimination from nontargeted organs, through urinary excretion. Fluorescence imaging gave similar results. On this basis, fluorescence-guided resection of tumor masses was successfully carried out on a preclinical model.