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Abstract

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.

Author information

Yoon HY1, Shin ML1,2, Shim MK1,3, Lee S1, Na JH4, Koo H5, Lee H4, Kim JH3, Lee KY2, Kim K1,6, Kwon IC1,6.​

1Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.2Department of Bioengineering, Hanyang University , 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.3Department of Pharmacy, Graduate School, Kyung Hee University , 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.4College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.5Department of Medical Lifescience, College of Medicine, The Catholic University of Korea , 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.6KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.