A new bioluminescent reporter system to study the biodistribution of systematically injected tumor-derived bioluminescent extracellular vesicles in mice
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Prakash Gangadaran1, Xiu Juan Li1, Ho Won Lee1, Ji Min Oh1, Senthilkumar Kalimuthu1, Ramya Lakshmi Rajendran1, Seung Hyun Son1, Se Hwan Baek1, Thoudam Debraj Singh1,2, Liya Zhu1, Shin Young Jeong1, Sang-Woo Lee1, Jaetae Lee1 and Byeong-Cheol Ahn1
1Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, Daegu 700-721, Republic of Korea
2Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi 110029, India
Byeong-Cheol Ahn, email: [email protected]
Keywords: imaging; extracellular vesicle; bioluminescence; in vivo biodistribution; thyroid cancer
Received: February 16, 2017 Accepted: October 28, 2017 Published: November 18, 2017
In vivo biodistribution and fate of extracellular vesicles (EVs) are still largely unknown and require reliable in vivo tracking techniques. In this study, in vivo bioluminescence imaging (BLI) using Renilla luciferase (Rluc) was developed and applied to monitoring of EVs derived from thyroid cancer (CAL-62 cells) and breast cancer (MDA-MB-231) in nude mice after intravenous administration and was compared with a dye-based labeling method for EV derived from CAL-62 cells. The EVs were successfully labeled with Rluc and visualized by BLI in mice. In vivo distribution of the EVs, as measured by BLI, was consistent with the results of ex vivo organ analysis. EV-CAL-62/Rluc showed strong signals at lung followed by liver, spleen & kidney (P < 0.05). EV-MDA-MB-231/Rluc showed strong signals at liver followed by lung, spleen & kidney (P < 0.05). EV-CAL-62/Rluc and EV-MDA-MB-231/Rluc stayed in animal till day 9 and 3, respectively; showed a differential distribution. Spontaneous EV-CAL-62/Rluc shown distributed mostly to lung followed by liver, spleen & kidney. The new BLI system used to show spontaneous distribution of EV-CAL-62/Rluc in subcutaneous CAL-62/Rluc bearing mice. Dye (DiR)-labeled EV-CAL-62/Rluc showed a different distribution in vivo & ex vivo compared to EV-CAL-62/Rluc. Fluorescent signals were predominately detected in the liver (P < 0.05) and spleen (P < 0.05) regions. The bioluminescent EVs developed in this study may be used for monitoring of EVs in vivo. This novel reporter-imaging approach to visualization of EVs in real time is expected to pave the way for monitoring of EVs in EV-based treatments.
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