19 F magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique with demonstrated potential for the detection of important diseases. The major challenge in the design of 19 F MRI agents is signal attenuation caused by the reduced solubility and segmental mobility of probes with high numbers of fluorine atoms. Careful choice of the fluorinated moiety is required to maintain image quality at the fluorine contents required for high imaging sensitivity. Here we report the synthesis of perfluoropolyether (PFPE) end-functionalized homopolymers of oligo(ethylene glycol) methyl ether acrylate (poly(OEGA) m -PFPE) as highly sensitive 19 F MRI contrast agents (CAs). The structural characteristics, conformation and aggregation behavior, 19 F NMR relaxation properties, and 19 F MR imaging were studied in detail. Dynamic light scattering and molecular dynamics (MD) simulations were conducted and demonstrated that poly(OEGA) m -PFPE with the longest poly(OEGA) m segments (m = 20) undergoes single-chain folding in water while poly(OEGA) 10 -PFPE and poly(OEGA) 4 -PFPE with shorter OEGA segments experience multiple-chain aggregation. Long 19 F T 2 relaxation times were measured for all poly(OEGA) m -PFPE polymers in PBS and in the presence of serum (>80 ms), and no obvious decrease in 19 F T 2 was observed with increasing fluorine content up to ∼30 wt %. Moreover, the signal-to-noise ratio increased linearly with increasing concentration of fluorine, indicating that the PFPE-based polymers can be applied as quantitative tracers. Furthermore, we investigated the in vivo behavior, in particular their biodistribution, of the polymers with different aggregation properties. Control over the balance of hydrophobicity and hydrophilicity allows manipulation of the aggregation state, and this leads to different circulation behavior in a murine model. This first report of the synthesis of polymeric PFPE-based 19 F MRI CAs demonstrates that these polymers are an exciting new class of 19 F MRI CAs with extremely high fluorine content and outstanding imaging sensitivity.
N-linked glycosylation is one of the most important post-translational modifications of proteins. Current knowledge of multicellular eukaryote N-glycan biosynthesis suggests high mannose N-glycans are generated in the endoplasmic reticulum and Golgi apparatus through conserved biosynthetic pathways. According to conventional biosynthetic pathways, four Man7GlcNAc2 isomers, three Man6GlcNAc2 isomers, and one Man5GlcNAc2 isomer are generated during this process. In this study, we applied our latest mass spectrometry method, logically derived sequence tandem mass spectrometry (LODES/MS n ), to re-examine high mannose N-glycans extracted from various multicellular eukaryotes which are not glycosylation mutants. LODES/MS n identified many high mannose N-glycan isomers previously unreported in plantae, animalia, cancer cells, and fungi. A database consisting of retention time and CID MS n mass spectra was constructed for all possible Man n GlcNAc2 (n = 5, 6, 7) isomers that include the isomers by removing arbitrary numbers and positions of mannose from canonical N-glycan, Man9GlcNAc2. Many N-glycans in this database are not found in current N-glycan mass spectrum libraries. The database is useful for rapid high mannose N-glycan isomeric identification.
N-linked glycosylation is one of the most important post-translational modifications of proteins. Current knowledge of multicellular eukaryote N-glycan biosynthesis suggests high mannose N-glycans are generated in the endoplasmic reticulum and Golgi apparatus through conserved biosynthetic pathways. As a part of post-translational modifications, lipid dolichol-phosphate linked oligosaccharide Glc3Man9GlcNAc2 is transferred to proteins, and glucoses and mannose are sequentially removed by various ER- and Golgi-localized glucosidases and -1,2-mannosidases. According to reported biosynthetic pathways, four Man7GlcNAc2 isomers, three Man6GlcNAc2 isomers, and one Man5GlcNAc2 isomer are generated during this process. In this study, we applied our latest mass spectrometry method, logically derived sequence tandem mass spectrometry (LODES/MSn) to re-examine high mannose N-glycans extracted from various multicellular eukaryotes. LODES/MSn identified many high mannose N-glycan isomers previously unreported in plantae, animalia, cancer cells, and fungi. Importantly, their synthesis is yet described by known biosynthetic pathways, thereby suggesting additional and unidentified pathways for these N-glycans isomers in multicellular eukaryotic cells.
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