Development of pH/Glutathione-Responsive Theranostic Agents Activated by Glutathione S-Transferase π for Human Colon Cancer

J Med Chem. 2020 Sep 10;63(17):9271-9283. doi: 10.1021/acs.jmedchem.0c00354.

Ji Liu ¹, Xin Liu ¹, Jianqiang Qian ¹, Chi Meng ¹, Peng Zhu ¹ ², Jiaying Hang ¹, Yaling Wang ¹ ², Biao Xiong ¹, Xiaodong Qiu ¹, Weizhong Zhu ¹, Yumin Yang ¹, Yanan Zhang ¹, Yong Ling ¹ ²

Affiliations

1 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China.
2 Key Laboratory of Neuroregeneration, Ministry of Education and Jiangsu Province, Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, PR China.

PMID: 32787089 DOI: 10.1021/acs.jmedchem.0c00354

Abstract

Two novel theranostic agents HJTA and HJTB have been designed and synthesized by covalently linking a β-carboline derivative, with antitumor activities and pH-responsive fluorescence, with a 2-exomethylenecyclohexanone moiety, which can be activated by the tumor-targeting glutathione (GSH)/Glutathione S-transferase π (GSTπ). These agents showed pH- and GSH-dual-responsive fluorescence in tumor cells but not in normal cells. Importantly, HJTA selectively illuminated tumor tissue for up to 7 h and generated precise visualization of orthotopic colonic tumors through the blood circulation system in intraoperative mice. Furthermore, HJTA exhibited potent and selective antiproliferative activities and colonic tumor inhibition in mice. Finally, HJTA induced great Cancer cell Apoptosis and Autophagy by regulating the expression of apoptotic and autophagic proteins. Therefore, this pH/GSH-dual-responsive fluorescent probe with cancer-targeting therapeutic activity provides a novel tool for precise diagnosis and tumor treatment, therefore broadening the impact of multifunctional agents as theranostic precision medicines.

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