title: Artificial Chemical Reporter Targeting Strategy Using Bioorthogonal Click Reaction for Improving Active-Targeting Efficiency of Tumor.
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 αvβ3with 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.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Hong Yeol
authors.initials: HY
authors.lastname: Yoon
authors.affiliation: 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.
authors.forename: Min Lee
authors.initials: ML
authors.lastname: Shin
authors.affiliation: 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 Pharmacy, Graduate School, Kyung Hee University , 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Man Kyu
authors.initials: MK
authors.lastname: Shim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Na
authors.affiliation: Department of Medical Lifescience, College of Medicine, The Catholic University of Korea , 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Heebeom
authors.initials: H
authors.lastname: Koo
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Science, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.
authors.forename: Hyukjin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Graduate School, Kyung Hee University , 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Hanyang University , 222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
authors.forename: Kuen Yong
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Ick Chan
authors.identifier: 0000-0003-1272-7074
authors.initials: IC
authors.lastname: Kwon
mesh_terms: D001386:Azides / Q000737:chemistry; D001932:Brain Neoplasms / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry; D057930:Click Chemistry / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*
chemical_list: D001386:Azides; C118638:glycol-chitosan; D048271:Chitosan
keywords: active tumor targeting; bioorthogonal click reaction; heterogeneity; metabolic glycoengineering