Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy
10.1016/j.jpha.2023.02.010
- Author:
Xiangyi WANG
1
,
2
;
Jin ZHANG
;
Kailu ZHENG
;
Qianqian DU
;
Guocai WANG
;
Jianpeng HUANG
;
Yanhe ZHOU
;
Yan LI
;
Hongtao JIN
;
Jiuming HE
Author Information
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
- Keywords:
Mass spectrometry imaging;
Spatially resolved metabolomics;
Small molecule-drug conjugate;
Tumor metabolism;
Targeted tumor therapy
- From:
Journal of Pharmaceutical Analysis
2023;13(7):776-787
- CountryChina
- Language:Chinese
-
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 metab-olomics 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 devel-oping SMDCs for precise cancer therapy.
