An in situ self‐assembled peptide derivative for inhibition of glutathione synthesis and selective enhancement of tumor radiotherapy

Author:

Gong Xinyan1,Cui Benhang1,Li Paiyun2,Gao Jie13,Gao Yang1,Cai Xiaoyao1,Wang Hang1,Zhang Wenxue2,Yang Cuihong1ORCID

Affiliation:

1. Key Laboratory of Radiopharmacokinetics for Innovative Drugs Chinese Academy of Medical Sciences Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Tianjin China

2. Radiation Oncology Department Tianjin Medical University General Hospital Tianjin China

3. Department of Biomedical Engineering University of Groningen University Medical Center Groningen Groningen The Netherlands

Abstract

AbstractBackgroundInhibition of glutathione (GSH) synthesis in cancer cells considerably improves the efficacy of reactive oxygen species (ROS)‐related tumor therapy. Self‐assembled peptide derivatives can facilitate the efficient delivery and accumulation of small molecular drugs in cancer cells.MethodsSelf‐assembling modules were covalently linked to the GSH‐biosynthesis inhibitor l‐buthionine sulfoximine (BSO) by solid‐phase synthesis to form the self‐assembling peptide derivative Nap‐DFDFpY‐GG‐BSO (Nano‐BSO@ in situ). Subsequently, its enzyme‐instructed self‐assembly in vitro and on cell surfaces were confirmed, and its intracellular GSH depletion and radiotherapy‐sensitizing effects were determined.ResultsNano‐BSO@ in situ successfully self‐assembles into a hydrogel with a nanofibrous microstructure upon incubation with alkaline phosphatase (ALP) at a critical concentration of 9.84 μM. Furthermore, it selectively self‐assembles in situ on HeLa cells with high ALP expression. At a concentration of 50 μM, Nano‐BSO@ in situ decreases intracellular GSH levels by 80%, ∼2.3 times more than free BSO. Meanwhile, pretreatment of HeLa cells with 50 μM Nano‐BSO@ in situ for 24 h results in a radiotherapy sensitization enhancement ratio to γ‐rays of 2.09.ConclusionsA novel in situ self‐assembling peptide derivative for GSH depletion and selective enhancement of tumor radiotherapy was constructed. The excellent GSH‐depletion ability and remarkable radiotherapy‐enhancement performance indicate that Nano‐BSO@ in situ is a promising selective sensitizer for ROS‐related treatment of tumor cells with high ALP expression.

Funder

National Natural Science Foundation of China

Chinese Academy of Medical Sciences Initiative for Innovative Medicine

Publisher

Wiley

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