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 ([⁸⁹Zr]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 [⁸⁹Zr]Zr-labeled human umbilical cord MSC (hucMSC)-derived EVs to characterize the homing of EVs to tumor regions via PET imaging. The uptake of [⁸⁹Zr]Zr-DFO-hucMSC-EVs by 4T1, H292, and FaDu cells increased in a time-dependent manner. [⁸⁹Zr]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, [⁸⁹Zr]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 [⁸⁹Zr]Zr-DFO-hucMSC-EV tracer for noninvasive visualization of tumor lesions.