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그림1) A novel TIC probe TiNIR, which targets to HMOX2 in the tumor was developed and showed its feasibility as a tracking and therapeutic tool for lung cancer.

그림2) Target identification of TiNIR. Confirmation of TiNIR target by treatment of HMOX2 siRNA.

그림3) In vivo imaging of lung tumor metastasis mouse by MSOT (multispectral optoacoustic tomography).

그림4) Therapeutic effect of TiNIR on the lung cancer. Inhibition of tumor relapse by TiNIR. To check the relapse of the tumor, TS32 cells were injected into the flank site of NSG mice. Tumor tissues were removed by surgery in anesthesia by ketamine (40mg/kg) /xylazine (10mg/kg). From day 1 after post-surgery of tumors, TiNIR (100 μM) was injected into tail vein (200 μL/mouse) every couple of days until day 27.

Abstract
Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.

Author information

Kim JJ1,2, Lee YA1,3, Su D1, Lee J4, Park SJ1, Kim B1, Jane Lee JH3,5, Liu X2, Kim SS6, Bae MA6, Lee JS7, Hong SC7, Wang L1,8, Samanta A1,9, Kwon HY2, Choi SY, Kim JY10, Yu YH11, Ha HH11, Wang Z3, Tam WL3,12,13, Lim B3,14, Kang NY1,4, Chang YT1,2.
1
Laboratory of Bioimaging Probe Development, Singapore Bioimaging Consortium, Agency for Science , Technology and Research (A*STAR) , Singapore 138667 , Singapore.
2
Center for Self-assembly and Complexity , Institute for Basic Science (IBS) , Pohang 37673 , Republic of Korea.
3
Genome Institute of Singapore, Agency for Science , Technology and Research (A*STAR) , 60 Biopolis Street , Singapore 138672 , Singapore.
4
New Drug Discovery Center , DGMIF , Daegu 41061 , Republic of Korea.
5
School of Biological Sciences , Nanyang Technological University , Singapore 637551 , Singapore.
6
Bio & Drug Discovery Division , Korea Research Institute of Chemical Technology , Yuseong-Gu , Gajeong-ro 141 , Daejeon 34114 , Republic of Korea.
7
Molecular Recognition Research Center , Korea Institute of Science and Technology , 5, Hwarang-ro 14-gil , Seoul 02792 , Republic of Korea.
8
Department of Chemical Biology , Max Planck Institute for Medical Research , Heidelberg 69120 , Germany.
9
Chemical Sciences and Technology Division , CSIR - National Institute for Interdisciplinary Sciences and Technology (CSIR - NIIST) , Industrial Estate P O , Pappanamcode , Thiruvananthapuram 695019 , India.
10
A-fourth, SL VAXiGEN , KOREA BIO PARK , Daewangpangyo-ro 700, Bundang-gu , Seongnam-si , Gyenggi-do 13488 , Korea.
11
Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences 11 , Sunchon National University , Suncheon 57922 , Republic of Korea.
12
Cancer Science Institute of Singapore , National University of Singapore , Singapore 117599 , Singapore.
13
Department of Biochemistry, Yong Loo Lin School of Medicine , National University of Singapore , Singapore 117597 , Singapore.
14
Merck Sharp and Dohme Translational Medicine Research Centre , 8A Biomedical Grove , Singapore 138648 , Singapore.