Extracellular vesicles act as nano‐transporters of tyrosine kinase inhibitors to revert iodine avidity in thyroid cancer

A new approach for using extracellular vesicles (EVs) to deliver tyrosine kinase inhibitors (TKIs) to enhance iodine avidity in radioactive iodine‐refractory thyroid cancer is needed. We isolated and characterized primary human adipose‐derived stem cells (ADSCs) and isolated their EVs. The EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. A new TKI was loaded into the EVs by incubation (37 °C; 10 min) or sonication (18 cycles; 4 s per cycle) with 2 s intervals and a 2 min ice bath every six cycles. TKI loading was confirmed and measured by mass spectrometry. EV uptake into radioactive iodine-refractory thyroid cancer cells (SW1736 cells) was confirmed by microscopy. We treated the SW1736 cells with vehicle, TKI, or TKI‐loaded EVs (sonication TKI‐loaded EVs [EVs^TKI(S)]) and examined the expression of iodide‐metabolizing proteins and radioiodine uptake in the SW1736 cells. ADSCs cells showed >99% of typical stem cell markers, such as CD90 and CD105. The EVs displayed a round morphology, had an average size of 211.4 ± 3.83 nm, and were positive for CD81 and Alix and negative for cytochrome c. The mass spectrometry results indicate that the sonication method loaded ~4 times more of the TKI than did the incubation method. The EVs^TKI(S) were used for further experiments. Higher expression levels of iodide‐metabolizing mRNA and proteins in the EVs^TKI(S)‐ treated SW1736 cells than in TKI‐treated SW1736 cells were confirmed. EVs^TKI(S) treatment enhanced 12₅ I uptake in the recipient SW1736 cells compared with free‐TKI treatment. This is the first study that demonstrated successful delivery of a TKI to radioactive iodine‐refractory thyroid cancer cells using EVs as the delivery vehicle. This approach can revert radioiodine‐resistant thyroid cancer cells back to radioiodine‐sensitive thyroid cancer cells.