Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.

Wen LI; Jiali Huang; Chen Shen; Weiye Jiang; Xi Yang; Jingxuan Huang; Yueqing GU; Zhiyu LI; Yi MA; Jinlei Bian

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Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.

Author: Wen LI ¹ ; Jiali HUANG ¹ ; Chen SHEN ¹ ; Weiye JIANG ¹ ; Xi YANG ¹ ; Jingxuan HUANG ¹ ; Yueqing GU ¹ ; Zhiyu LI ¹ ; Yi MA ¹ ; Jinlei BIAN ¹
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1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Publication Type:Journal Article
Keywords: Cyanine dye; Glutamine antagonists; Immunotherapy; Metabolic inhibitor; Non-small-cell lung cancer (NSCLC); Photodynamic therapy; Reactive oxygen species; Smart prodrug system
From: Acta Pharmaceutica Sinica B 2024;14(2):751-764
CountryChina
Language:English
Abstract: Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.