2. Academic Validation
  3. Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity

Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity

  • Eur J Med Chem. 2024 Jan 15:264:115988. doi: 10.1016/j.ejmech.2023.115988.
Wenchong Ye 1,  Qun Tang 2,  Tiantian Zhou 2,  Cui Zhou 3,  Chuangchuang Fan 2,  Xiaoyang Wang 2,  Chunmei Wang 2,  Keyu Zhang 2,  Guochao Liao 4,  Wen Zhou 5
Affiliations

Affiliations

  • 1 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, Guangdong, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China.
  • 2 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 3 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, 510006, China.
  • 4 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, Guangdong, China. Electronic address: gcliao@gzcmu.com.cn.
  • 5 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China. Electronic address: zhouwen60@126.com.
PMID: 38039790 DOI: 10.1016/j.ejmech.2023.115988
Abstract

Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively. The fluorescence intensity of Gal-Cy5.0 conjugates accumulated in Cancer cells hinted the optimal modification sites of positions C2 and C6. Comparing to the cytotoxicity of other conjugates, C2-Gal-Dox (11) was the most potent. Moreover, Gal-Dox conjugates significantly the toxicity of Dox. A progressively lower internalization capacity and siRNA technology implied the cellular uptake and cytotoxicity directly related to the ASGPR expression level. Accordingly, position C2 of galactose may be the best substitution site via ASGPR mediation in the design of anti-HCC glycoconjugates.

Keywords

ASGPR; Galactose; Glycoconjugates; Hepatocellular carcinoma; Positional isomer.

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