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Biomaterials. 2017 Sep;139:12-29. doi: 10.1016/j.biomaterials.2017.05.050. Epub 2017 Jun 1.

In vivo stem cell tracking with imageable nanoparticles that bind bioorthogonal chemical receptors on the stem cell surface.

Author information

1
Department of Pharmacy, College of Pharmacy, Wonkwang University, 460 Iksandae-ro, Iksan, Jeonbuk, 54538, Republic of Korea.
2
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea; Department of Chemical Engineering and Bionanotechnology, Hanyang University, 1271 Sa 3-dong, Sangnok-gu, Ansan, Gyeonggi-do, 15588, Republic of Korea.
3
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N. Caroline Street, Baltimore, MD, 21287, USA.
4
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea; School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
5
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea; School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
6
Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
7
Predictive Model Research Center, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea.
8
Department of Medicine, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
9
School of Chemical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
10
Department of Chemical Engineering and Bionanotechnology, Hanyang University, 1271 Sa 3-dong, Sangnok-gu, Ansan, Gyeonggi-do, 15588, Republic of Korea.
11
School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
12
Laboratory Animal Center, DGMIF (Daegu-Gyeongbuk, Medical Innovation Foundation), 80 Cheombok-ro, Dong-gu, Daegu, 41061, Republic of Korea.
13
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N. Caroline Street, Baltimore, MD, 21287, USA.
14
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.
15
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 1 Anam-dong, Seongbuk-gu, Seoul, 02841, Republic of Korea. Electronic address: kim@kist.re.kr.

Abstract

It is urgently necessary to develop reliable non-invasive stem cell imaging technology for tracking the in vivo fate of transplanted stem cells in living subjects. Herein, we developed a simple and well controlled stem cell imaging method through a combination of metabolic glycoengineering and bioorthogonal copper-free click chemistry. Firstly, the exogenous chemical receptors containing azide (-N3) groups were generated on the surfaces of stem cells through metabolic glycoengineering using metabolic precursor, tetra-acetylated N-azidoacetyl-d-mannosamine(Ac4ManNAz). Next, bicyclo[6.1.0]nonyne-modified glycol chitosan nanoparticles (BCN-CNPs) were prepared as imageable nanoparticles to deliver different imaging agents. Cy5.5, iron oxide nanoparticles and gold nanoparticles were conjugated or encapsulated to BCN-CNPs for optical, MR and CT imaging, respectively. These imageable nanoparticles bound chemical receptors on the Ac4ManNAz-treated stem cell surface specifically via bioorthogonal copper-free click chemistry. Then they were rapidly taken up by the cell membrane turn-over mechanism resulting in higher endocytic capacity compared non-specific uptake of nanoparticles. During in vivo animal test, BCN-CNP-Cy5.5-labeled stem cells could be continuously tracked by non-invasive optical imaging over 15 days. Furthermore, BCN-CNP-IRON- and BCN-CNP-GOLD-labeled stem cells could be efficiently visualized using in vivo MR and CT imaging demonstrating utility of our stem cell labeling method using chemical receptors. These results conclude that our method based on metabolic glycoengineering and bioorthogonal copper-free click chemistry can stably label stem cells with diverse imageable nanoparticles representing great potential as new stem cell imaging technology.

KEYWORDS:

Bioorthogonal copper-free click chemistry; Chemical receptors; Metabolic glycoengineering; Stem cell imaging; Unnatural sialic acids

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