title: Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy.
abstract: Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy.
authors.affiliation: College of Pharmaceutical Science, Jilin University, Changchun 130021, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ding
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Ji
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiaozheng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zhao
authors.affiliation: College of Pharmaceutical Science, Jilin University, Changchun 130021, China. Electronic address: jingyanweijluedu@163.com.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Wei
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, Norfolk NR4 7TJ, UK. Electronic address: Sheng.Qi@uea.ac.uk.
authors.forename: Sheng
authors.initials: S
authors.lastname: Qi
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), 11 Beiyitiao, Zhongguancun, Beijing 100190, China. Electronic address: niegj@nanoctr.cn.
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
mesh_terms: D000469:Alkaline Phosphatase / Q000737:chemistry; D004999:Amifostine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity; D019610:Cytoprotection; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D000469:Alkaline Phosphatase; D004999:Amifostine; D002945:Cisplatin
keywords: Amifostine; Antioxidant; Chemoprotection; Chemotherapy; PEGylation