ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
Recently Viewed
You have not visited any articles yet, Please visit some articles to see contents here.

Figure 1Loading Img

Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor

View Author Information
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea
Department of Bioengineering, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
§ Department of Pharmacy, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
# KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea
Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
*Tel: +82-2-958-5912. Fax: +82-2-958-5909. E-mail: [email protected]
*Tel: +82-2-958-5916. Fax: +82-2-958-5909. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2017, 14, 5, 1558–1570
Publication Date (Web):February 13, 2017
Copyright © 2017 American Chemical Society
Article Views
Read OnlinePDF (2 MB)
Supporting Info (1)»


Abstract Image

Biological ligands such as aptamer, antibody, glucose, and peptide have been widely used to bind specific surface molecules or receptors in tumor cells or subcellular structures to improve tumor-targeting efficiency of nanoparticles. However, this active-targeting strategy has limitations for tumor targeting due to inter- and intraheterogeneity of tumors. In this study, we demonstrated an alternative active-targeting strategy using metabolic engineering and bioorthogonal click reaction to improve tumor-targeting efficiency of nanoparticles. We observed that azide-containing chemical reporters were successfully generated onto surface glycans of various tumor cells such as lung cancer (A549), brain cancer (U87), and breast cancer (BT-474, MDA-MB231, MCF-7) via metabolic engineering in vitro. In addition, we compared tumor targeting of artificial azide reporter with bicyclononyne (BCN)-conjugated glycol chitosan nanoparticles (BCN–CNPs) and integrin αvβ3 with cyclic RGD-conjugated CNPs (cRGD–CNPs) in vitro and in vivo. Fluorescence intensity of azide-reporter-targeted BCN–CNPs in tumor tissues was 1.6-fold higher and with a more uniform distribution compared to that of cRGD–CNPs. Moreover, even in the isolated heterogeneous U87 cells, BCN–CNPs could bind artificial azide reporters on tumor cells more uniformly (∼92.9%) compared to cRGD–CNPs. Therefore, the artificial azide-reporter-targeting strategy can be utilized for targeting heterogeneous tumor cells via bioorthogonal click reaction and may provide an alternative method of tumor targeting for further investigation in cancer therapy.

Supporting Information

Jump To

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.6b01083.

  • MFI results and images of U87 tumor cells (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

Cited By

This article is cited by 31 publications.

  1. Ludivine Taiariol, Carole Chaix, Carole Farre, Emmanuel Moreau. Click and Bioorthogonal Chemistry: The Future of Active Targeting of Nanoparticles for Nanomedicines?. Chemical Reviews 2022, 122 (1) , 340-384.
  2. Fangfang Wang, Hong Pan, Xiangjie Yao, Huamei He, Lanlan Liu, Yingmei Luo, Haimei Zhou, Mingbin Zheng, Renli Zhang, Yifan Ma, Lintao Cai. Bioorthogonal Metabolic Labeling Utilizing Protein Biosynthesis for Dynamic Visualization of Nonenveloped Enterovirus 71 Infection. ACS Applied Materials & Interfaces 2020, 12 (3) , 3363-3370.
  3. Peng Zhang, Xiaoke Zhang, Cheng Li, Sensen Zhou, Wei Wu, Xiqun Jiang. Target-Amplified Drug Delivery of Polymer Micelles Bearing Staudinger Ligation. ACS Applied Materials & Interfaces 2019, 11 (36) , 32697-32705.
  4. Lihua Du, Huan Qin, Teng Ma, Tao Zhang, and Da Xing . In Vivo Imaging-Guided Photothermal/Photoacoustic Synergistic Therapy with Bioorthogonal Metabolic Glycoengineering-Activated Tumor Targeting Nanoparticles. ACS Nano 2017, 11 (9) , 8930-8943.
  5. Yang Ding, Yue Han, Ruoning Wang, Yazhe Wang, Cheng Chi, Ziqiang Zhao, Huaqing Zhang, Wei Wang, Lifang Yin, and Jianping Zhou . Rerouting Native HDL to Predetermined Receptors for Improved Tumor-Targeted Gene Silencing Therapy. ACS Applied Materials & Interfaces 2017, 9 (36) , 30488-30501.
  6. Fang Li, Yan Zhao, Chengqiong Mao, Yi Kong, and Xin Ming . RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer. Molecular Pharmaceutics 2017, 14 (8) , 2793-2804.
  7. Haiming Luo, Christopher G. England, Shreya Goel, Stephen A. Graves, Fanrong Ai, Bai Liu, Charles P. Theuer, Hing C. Wong, Robert J. Nickles, and Weibo Cai . ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment. Molecular Pharmaceutics 2017, 14 (5) , 1646-1655.
  8. Hong Yeol Yoon, Donghyun Lee, Dong‐Kwon Lim, Heebeom Koo, Kwangmeyung Kim. Copper‐Free Click Chemistry: Applications in Drug Delivery, Cell Tracking, and Tissue Engineering. Advanced Materials 2022, 34 (10) , 2107192.
  9. Yi Yan, Xiao-Yu Liu, An Lu, Xiang-Yu Wang, Lin-Xia Jiang, Jian-Cheng Wang. Non-viral vectors for RNA delivery. Journal of Controlled Release 2022, 342 , 241-279.
  10. Zichao Luo, Dehong Hu, Duyang Gao, Zhigao Yi, Hairong Zheng, Zonghai Sheng, Xiaogang Liu. High‐Specificity In Vivo Tumor Imaging Using Bioorthogonal NIR‐IIb Nanoparticles. Advanced Materials 2021, 33 (49) , 2102950.
  11. Xunfa Zhang, Yang Chen, Xian He, Yachao Zhang, Mei Zhou, Chengjun Peng, Zhonggui He, Shuangying Gui, Zhenbao Li. Smart Nanogatekeepers for Tumor Theranostics. Small 2021, 17 (47) , 2103712.
  12. Ke Kang, Xiaoxi Zhou, Yujia Zhang, Nanhang Zhu, Guohao Li, Qiangying Yi, Yao Wu. Cell‐Released Magnetic Vesicles Capturing Metabolic Labeled Rare Circulating Tumor Cells Based on Bioorthogonal Chemistry. Small 2021, 17 (18) , 2007796.
  13. Javier Idiago-López, Eduardo Moreno-Antolín, Jesús M. de la Fuente, Raluca M. Fratila. Nanoparticles and bioorthogonal chemistry joining forces for improved biomedical applications. Nanoscale Advances 2021, 3 (5) , 1261-1292.
  14. Maria Victoria Cano-Cortes, Patricia Altea-Manzano, Jose Antonio Laz-Ruiz, Juan Diego Unciti-Broceta, Francisco Javier Lopez-Delgado, Jose Manuel Espejo-Roman, Juan Jose Diaz-Mochon, Rosario M. Sanchez-Martin. An effective polymeric nanocarrier that allows for active targeting and selective drug delivery in cell coculture systems. Nanoscale 2021, 13 (6) , 3500-3511.
  15. Woojun Kim, Hong Yeol Yoon, Seungho Lim, Patrick S. Stayton, In-San Kim, Kwangmeyung Kim, Ick Chan Kwon. In vivo tracking of bioorthogonally labeled T-cells for predicting therapeutic efficacy of adoptive T-cell therapy. Journal of Controlled Release 2021, 329 , 223-236.
  16. Ju Hee Ryu, Hong Yeol Yoon, In‐Cheol Sun, Ick Chan Kwon, Kwangmeyung Kim. Tumor‐Targeting Glycol Chitosan Nanoparticles for Cancer Heterogeneity. Advanced Materials 2020, 32 (51) , 2002197.
  17. Hua Wang, David J. Mooney. Metabolic glycan labelling for cancer-targeted therapy. Nature Chemistry 2020, 12 (12) , 1102-1114.
  18. Yalan Tu, Yansong Dong, Kewei Wang, Song Shen, Youyong Yuan, Jun Wang. Intercellular delivery of bioorthogonal chemical receptors for enhanced tumor targeting and penetration. Biomaterials 2020, 259 , 120298.
  19. En Ren, Chengchao Chu, Yunming Zhang, Junqing Wang, Xin Pang, Xiaoning Lin, Chao Liu, Xiaoxiao Shi, Qixuan Dai, Peng Lv, Xiaomin Wang, Xiaoyuan Chen, Gang Liu. Mimovirus Vesicle‐Based Biological Orthogonal Reaction for Cancer Diagnosis. Small Methods 2020, 4 (9) , 2000291.
  20. Wei Mao, Young Ju Son, Hyuk Sang Yoo. Gold nanospheres and nanorods for anti-cancer therapy: comparative studies of fabrication, surface-decoration, and anti-cancer treatments. Nanoscale 2020, 12 (28) , 14996-15020.
  21. Kyeong Cheol On, Jiyun Rho, Hong Yeol Yoon, Hyeyoun Chang, Ji Young Yhee, Jun Sik Yoon, Seo Young Jeong, Hyun Koo Kim, Kwangmeyung Kim. Tumor-Targeting Glycol Chitosan Nanoparticles for Image-Guided Surgery of Rabbit Orthotopic VX2 Lung Cancer. Pharmaceutics 2020, 12 (7) , 621.
  22. Yunxia Wu, Judun Zheng, Da Xing, Tao Zhang. Near-infrared light controlled fluorogenic labeling of glycoengineered sialic acids in vivo with upconverting photoclick nanoprobe. Nanoscale 2020, 12 (18) , 10361-10368.
  23. Elena las Heras, Ester Boix‐Garriga, Francesca Bryden, Montserrat Agut, Margarita Mora, M. Lluïsa Sagristá, Ross W. Boyle, Norbert Lange, Santi Nonell. c(RGDfK)‐ and ZnTriMPyP‐Bound Polymeric Nanocarriers for Tumor‐Targeted Photodynamic Therapy. Photochemistry and Photobiology 2020, 96 (3) , 570-580.
  24. Sajjad Molavipordanjani, Seyed Jalal Hosseinimehr. Strategies for Conjugation of Biomolecules to Nanoparticles as Tumor Targeting Agents. Current Pharmaceutical Design 2019, 25 (37) , 3917-3926.
  25. Fengming Lin, Hao-Ran Jia, Fu-Gen Wu. Glycol Chitosan: A Water-Soluble Polymer for Cell Imaging and Drug Delivery. Molecules 2019, 24 (23) , 4371.
  26. Yongwhan Choi, Seungho Lim, Hong Yeol Yoon, Byung-Soo Kim, Ick Chan Kwon, Kwangmeyung Kim. Tumor-targeting glycol chitosan nanocarriers: overcoming the challenges posed by chemotherapeutics. Expert Opinion on Drug Delivery 2019, 16 (8) , 835-846.
  27. Hyosuk Kim, Gijung Kwak, Kwangmeyung Kim, Hong Yeol Yoon, Ick Chan Kwon. Theranostic designs of biomaterials for precision medicine in cancer therapy. Biomaterials 2019, 213 , 119207.
  28. Pengfei Zhang, Tao Jiang, Yuanyuan Li, Zheng Zhao, Ping Gong, Lintao Cai, Ryan T. K. Kwok, Jacky Wing Yip Lam, Xinggui Gu, Ben Zhong Tang. Bio‐orthogonal AIE Dots Based on Polyyne‐Bridged Red‐emissive AIEgen for Tumor Metabolic Labeling and Targeted Imaging. Chemistry – An Asian Journal 2019, 14 (6) , 770-774.
  29. Wenjun Li, Hong Pan, Huamei He, Xiaoqing Meng, Qian Ren, Ping Gong, Xin Jiang, Zhenguo Liang, Lanlan Liu, Mingbin Zheng, Ximing Shao, Yifan Ma, Lintao Cai. Bio-Orthogonal T Cell Targeting Strategy for Robustly Enhancing Cytotoxicity against Tumor Cells. Small 2019, 15 (4) , 1804383.
  30. Khaled Seidi, Heidi A. Neubauer, Richard Moriggl, Rana Jahanban-Esfahlan, Tahereh Javaheri. Tumor target amplification: Implications for nano drug delivery systems. Journal of Controlled Release 2018, 275 , 142-161.
  31. Man Kyu Shim, Hong Yeol Yoon, Sangmin Lee, Mun Kyeong Jo, Jooho Park, Jong-Ho Kim, Seo Young Jeong, Ick Chan Kwon, Kwangmeyung Kim. Caspase-3/-7-Specific Metabolic Precursor for Bioorthogonal Tracking of Tumor Apoptosis. Scientific Reports 2017, 7 (1)

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Your Mendeley pairing has expired. Please reconnect

This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.