title: Synthesis and Characterization of PEGylated Trityl Radicals: Effect of PEGylation on Physicochemical Properties.
abstract: Tetrathiatriarylmethyl (TAM, trityl) radicals have attracted considerable attention as spin probes for biological electron paramagnetic resonance (EPR) spectroscopy and imaging owing to their sharp EPR singlet signals and high biostability. However, their in vivo applications were limited by the short blood circulation lifetimes and strong binding with albumins. Our previous results showed that PEGylation is a feasible method to overcome the issues facing in vivo applications of TAM radicals. In the present study, we synthesized a series of new PEGylated TAM radicals (TTP1, TPP2, TNP1, TNP2, d-TNP1, and d-TNP3) containing various lengths and numbers of mPEG chains. Our results found that the pattern of PEGylation exerts an important effect on physicochemical properties of the resulting TAM radicals. Dendritic PEGylated TAM radicals, TNP1 and TNP2, have higher water solubility and lower susceptibility for self-aggregation than their linear analogues TPP1 and TPP2. Furthermore, dendritic PEGylated TAM radicals exhibit extremely high stability toward various biological oxidoreductants as well as in rat whole blood, liver homogenate, and following in vivo intravenous administration in mice. Importantly, the deuterated derivatives, especially d-TNP3, exhibit excellent properties including the sharp and O2-sensitive EPR singlet signal, good biocompatibility, and prolonged kinetics with half-life time of ≥10 h in mice. These PEGylated TAM radicals should be suitable for a wide range of applications in in vivo EPR spectroscopy and imaging.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Nie
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Tan
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Yu
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Han
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, P. R. China.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Villamena
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Center for Biomedical EPR Spectroscopy and Imaging, The Davis Heart and Lung Research Institute, the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.|Center for Biomedical EPR Spectroscopy and Imaging, The Davis Heart and Lung Research Institute, the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Yangping
authors.identifier: 0000-0001-5455-3602
authors.initials: Y
authors.lastname: Liu
mesh_terms: D005609:Free Radicals / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry*; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D005609:Free Radicals; D014320:Triphenylmethyl Compounds; D011092:Polyethylene Glycols