Construction of [89Zr]Zr-Labeled Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles for Noninvasive Detection of Tumors

Extracellular vesicles (EVs) act as carriers that transfer molecules between donor and recipient cells, thereby altering the phenotype and function of the latter. EVs derived from mesenchymal stem cells (MSCs) inherit the homing ability of their parent cells to tumor sites. We speculate that MSC-derived EVs labeled with the isotope zirconium-89 ([ 89 Zr]Zr) will accumulate within tumors and have the potential for tumor location via positron emission tomography (PET) imaging. Here, as a proof of concept, we used [ 89 Zr]Zr-labeled human umbilical cord MSC (hucMSC)-derived EVs to characterize the homing of EVs to tumor regions via PET imaging. The uptake of [ 89 Zr]Zr-DFO-hucMSC-EVs by 4T1, H292, and FaDu cells increased in a time-dependent manner. [ 89 Zr]Zr-DFO-hucMSC-EVs were rapidly cleared from the blood circulation, showing a 2-phase exponential decay with a biodistribution half-life of 0.46 h and an elimination-phase half-life of 11.87 h. At 24 h postinjection, [ 89 Zr]Zr-DFO-hucMSC-EVs were mainly distributed in the liver (10.39 ± 0.52%ID/g) and, to a lesser extent, in the spleen (9.87 ± 0.87%ID/g). PET imaging in tumor-bearing mouse models revealed persistently high tumor accumulation. The projected effective dose for an adult human female was low and was 0.084 mSv/MBq. There was no obvious normal tissue toxicity following the administration of excessive radioactivity. In summary, these studies demonstrate the potential feasibility of using the [ 89 Zr]Zr-DFO-hucMSC-EV tracer for noninvasive visualization of tumor lesions.