Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Xiangyi Wang; Jin Zhang; Kailu Zheng; Qianqian Du; Guocai Wang; Jianpeng Huang; Yanhe Zhou; Yan Li; Hongtao Jin; Jiuming He

doi:10.1016/j.jpha.2023.02.010

Volume 13 Issue 7

Jul. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(7): 776-787

Xiangyi Wang, Jin Zhang, Kailu Zheng, Qianqian Du, Guocai Wang, Jianpeng Huang, Yanhe Zhou, Yan Li, Hongtao Jin, Jiuming He. Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 776-787. doi: 10.1016/j.jpha.2023.02.010

Citation:

Xiangyi Wang, Jin Zhang, Kailu Zheng, Qianqian Du, Guocai Wang, Jianpeng Huang, Yanhe Zhou, Yan Li, Hongtao Jin, Jiuming He. Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 776-787. doi: 10.1016/j.jpha.2023.02.010

Citation:

Xiangyi Wang, Jin Zhang, Kailu Zheng, Qianqian Du, Guocai Wang, Jianpeng Huang, Yanhe Zhou, Yan Li, Hongtao Jin, Jiuming He. Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 776-787. doi: 10.1016/j.jpha.2023.02.010

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Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

doi: 10.1016/j.jpha.2023.02.010

Xiangyi Wang^a,b,
Jin Zhang^a,b,
Kailu Zheng^c,
Qianqian Du^c,
Guocai Wang^a,b,
Jianpeng Huang^a,b,
Yanhe Zhou^a,b,
Yan Li^{c
,
,},
Hongtao Jin^b,d,
Jiuming He^{a,b
,
,}

a. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China;
b. NMPA Key Laboratory of Safety Research and Evaluation of Innovative Drug, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China;
c. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China;
d. New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

Funds:

We thank Peking Union Medical College Hospital for providing clinical lung cancer tissue samples after surgery. We also would like to thank Beijing Union-Genius Pharmaceutical Technology Development Co., Ltd. for performing toxicity experiment and BioDuro Shanghai Co., Ltd. for synthesis of modified taxane compounds. This work was supported by the National Natural Science Foundation of China (Grant Nos.: 81974500 and 81773678), and the CAMS Innovation Fund for Medical Sciences (Grant No.: 2022-I2M-2-001).

Received Date: Nov. 18, 2022
Accepted Date: Feb. 23, 2023
Rev Recd Date: Feb. 19, 2023
Publish Date: Feb. 28, 2023

Abstract

Abstract

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy. However, metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity. Herein, choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types, and a choline-modified strategy for small molecule-drug conjugates (SMDCs) design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy, instead of directly inhibiting choline metabolism. As a proof-of-concept, choline-modified SMDCs were designed, screened, and investigated for their druggability in vitro and in vivo. This strategy improved tumor targeting, preserved tumor inhibition and reduced toxicity of paclitaxel, through targeted drug delivery to tumor by highly expressed choline transporters, and site-specific release by carboxylesterase. This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.
- Mass spectrometry imaging,
- Spatially resolved metabolomics,
- Small molecule-drug conjugate,
- Tumor metabolism,
- Targeted tumor therapy

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