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

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

J Pharm Anal. 2023 Jul;13(7):776-787. doi: 10.1016/j.jpha.2023.02.010. Epub 2023 Feb 28.

Authors

Xiangyi Wang^{1

2}, Jin Zhang^{1

2}, Kailu Zheng³, Qianqian Du³, Guocai Wang^{1

2}, Jianpeng Huang^{1

2}, Yanhe Zhou^{1

2}, Yan Li³, Hongtao Jin^{2

4}, Jiuming He^{1

2}

Affiliations

¹ 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.
² 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.
³ 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.
⁴ New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

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.

Keywords: Mass spectrometry imaging; Small molecule-drug conjugate; Spatially resolved metabolomics; Targeted tumor therapy; Tumor metabolism.