Extracellular Vesicles Act as Nano-Transporters of Tyrosine Kinase Inhibitors to Revert Iodine Avidity in Thyroid Cancer

• Main Authors: Ramya Lakshmi Rajendran, Sanjita Paudel, Prakash Gangadaran, Ji Min Oh, Eun Jung Oh, Chae Moon Hong, Sangkyu Lee, Ho Yun Chung, Jaetae Lee, Byeong-Cheol Ahn
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Pharmaceutics
• Subjects: extracellular vesicles; tyrosine kinase inhibitor; drug delivery; radioactive iodine; thyroid cancer
• Online Access: https://www.mdpi.com/1999-4923/13/2/248

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 ¹²⁵I 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.