title: Design of protein homocystamides with enhanced tumor uptake properties for (19)F magnetic resonance imaging.
abstract: Straightforward and reliable tools for in vivo imaging of tumors can benefit the studies of cancer development, as well as contribute to successful diagnosis and treatment of cancer. (19)F NMR offers an exceptional quantitative way of in vivo imaging of the infused agents because of the lack of (19)F signals from the endogenous molecules in the body. The purpose of this study is to develop molecular probes with appropriate NMR characteristics and the biocompatibility for in vivo applications using (19)F MRI. We have studied the reaction between perfluorotoluene and homocysteine thiolactone resulting in the formation of N-substituted homocysteine thiolactone derivative. It has been shown that the reaction occurs selectively at the para position. This fluorine-labeled homocysteine thiolactone has been employed for the introduction of a perfluorotoluene group as a (19)F-containing tag into human serum albumin. The modified protein has been studied in terms of its ability to aggregate and promote the formation of free radicals. By comparing the properties of N-perfluorotoluene-homocystamide of albumin with N-homocysteinylated albumin, it has been revealed that blocking of the alpha-amino group of the homocysteine residue in the fluorinated albumin conjugate inhibits the dangerous aggregation process, as well as free radical formation. A dual-labeled albumin-based molecular probe for (19)F MRI and fluorescence microscopy has been obtained by functionalizing the protein with both maleimide of a fluorescent dye and a fluorinated thiolactone derivative. The incubation of cells with this conjugate did not reveal any significant reduction in cell viability with respect to the parent albumin. The perfluorotoluene-labeled albumin has been demonstrated to act as a promising agent for in vivo (19)F MRI.
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, SB RAS, 630090 Novosibirsk, Russia; Novosibirsk State University, 630090 Novosibirsk, Russia.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Chubarov
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Olga D
authors.initials: OD
authors.lastname: Zakharova
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Koval
authors.affiliation: Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Romaschenko
authors.affiliation: Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Akulov
authors.affiliation: Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Evgenii L
authors.initials: EL
authors.lastname: Zavjalov
authors.affiliation: Institute of Cytology and Genetics, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Razumov
authors.affiliation: International Tomography Center, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Koptyug
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, SB RAS, 630090 Novosibirsk, Russia.
authors.forename: Dmitry G
authors.initials: DG
authors.lastname: Knorre
authors.affiliation: Institute of Chemical Biology and Fundamental Medicine, SB RAS, 630090 Novosibirsk, Russia; Novosibirsk State University, 630090 Novosibirsk, Russia. Electronic address: godov@niboch.nsc.ru.
authors.forename: Tatyana S
authors.initials: TS
authors.lastname: Godovikova
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D015195:Drug Design; D005260:Female; D066235:Fluorine-19 Magnetic Resonance Imaging; D005609:Free Radicals / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging; D011859:Radiography; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D003287:Contrast Media; D005609:Free Radicals; C502359:N-homocysteinylated albumin; D012709:Serum Albumin; D006710:Homocysteine; C007957:homocysteine thiolactone
keywords: Dual-labeled albumin-based molecular probe; Fluorinated homocysteine thiolactone; Fluorine magnetic resonance imaging; Glioma model; Homocysteine thiolactone; Human serum albumin; N-homocysteinylation; Perfluorotoluene; Protein aggregation; Thiyl radical