Drug Targeting Mini-Symposium of the Division for Medicinal Chemistry (DMC) of the Swiss Chemical Society (SCS), at the Department of Chemistry, University of Basel, May 29, 2008: Conference Report

Specific targeting of drugs to their respective target organs or tissues is challenging. Substantial research efforts have been undertaken in the recent past to develop target specific drugs or drug conjugates. Such concepts are most relevant in rather severe diseases like cancer since it helps to reduce the concentration of frequently rather toxic drugs outside the tumor tissue. Various techniques can be used to specifically direct a drug or a drug conjugate to a specific tumor tissue such as using antibodies directed against tumor specific proteins, as nanoparticles or nano-sized polymer conjugates carrying tumor-specific recognition elements or by applying the active drug principle in a prodrug form designed to be liberated specifically in tumor tissue. Three speakers from the academia and one speaker from industry described different approaches and their respective potentials from various perspectives in the lectures entitled: 'Polymer Therapeutics and other Nanomedicines as Targetable Cancer Therapies', 'Design, Application, and Chemical Biology of Tumor-Targeting Drug Conjugates', 'Antibody-Based Vascular Tumor Targeting: From the Bench to the Clinic', and 'Discovery of Capecitabine, a Rationally Designed and Tumor-Activated Oral Prodrug of 5-FU, and Beyond'

1,2,3-Tri-O-acetyl-5-de­oxy-d-ribofuran­ose

The title compound, C11H16O7, was obtained from the breakage reaction of the glycosidic bond of 5′-de­oxy-2′,3′-diacetyl­inosine. The ribofuran­ose ring has a C2-exo, C3-endo twist configuration. No alteration of the relative configuration compared with d-(−)-ribose is observed

Imaging Mass Spectrometry Technology and Application on Ganglioside Study; Visualization of Age-Dependent Accumulation of C20-Ganglioside Molecular Species in the Mouse Hippocampus

Gangliosides are particularly abundant in the central nervous system (CNS) and thought to play important roles in memory formation, neuritogenesis, synaptic transmission, and other neural functions. Although several molecular species of gangliosides have been characterized and their individual functions elucidated, their differential distribution in the CNS are not well understood. In particular, whether the different molecular species show different distribution patterns in the brain remains unclear. We report the distinct and characteristic distributions of ganglioside molecular species, as revealed by imaging mass spectrometry (IMS). This technique can discriminate the molecular species, raised from both oligosaccharide and ceramide structure by determining the difference of the mass-to-charge ratio, and structural analysis by tandem mass spectrometry. Gangliosides in the CNS are characterized by the structure of the long-chain base (LCB) in the ceramide moiety. The LCB of the main ganglioside species has either 18 or 20 carbons (i.e., C18- or C20-sphingosine); we found that these 2 types of gangliosides are differentially distributed in the mouse brain. While the C18-species was widely distributed throughout the frontal brain, the C20-species selectively localized along the entorhinal-hippocampus projections, especially in the molecular layer (ML) of the dentate gyrus (DG). We revealed development- and aging-related accumulation of the C-20 species in the ML-DG. Thus it is possible to consider that this brain-region specific regulation of LCB chain length is particularly important for the distinct function in cells of CNS

Mass spectrometry imaging of the capsaicin localization in the capsicum fruits

We succeeded in performing mass spectrometry imaging (MSI) of the localization of capsaicin in cross-sections of the capsicum fruits at a resolution of 250 µm using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Post source decay of protonated capsaicin ion revealed structural information of the corresponding acid amide of vanillylamide and C9 chain fatty acid. MALDI-TOF-MSI confirmed that localization of capsaicin in the placenta is higher than that in the pericarp. In addition, it revealed no localization of capsaicin in seed and the higher localization of capsaicin at placenta surface compared with that in the internal region. A quantitative difference was detected between localizations of capsaicin at placenta, pericarp and seed in the capsicum fruits. This imaging approach is a promising technique for rapid quality evaluation general food as well as health food and identification of medicinal capsaicin in plant tissues

Imaging Mass Spectrometry Technology and Application on Ganglioside Study; Visualization of Age-Dependent Accumulation of C20-Ganglioside Molecular Species in the Mouse Hippocampus

Gangliosides are particularly abundant in the central nervous system (CNS) and thought to play important roles in memory formation, neuritogenesis, synaptic transmission, and other neural functions. Although several molecular species of gangliosides have been characterized and their individual functions elucidated, their differential distribution in the CNS are not well understood. In particular, whether the different molecular species show different distribution patterns in the brain remains unclear. We report the distinct and characteristic distributions of ganglioside molecular species, as revealed by imaging mass spectrometry (IMS). This technique can discriminate the molecular species, raised from both oligosaccharide and ceramide structure by determining the difference of the mass-to-charge ratio, and structural analysis by tandem mass spectrometry. Gangliosides in the CNS are characterized by the structure of the long-chain base (LCB) in the ceramide moiety. The LCB of the main ganglioside species has either 18 or 20 carbons (i.e., C18- or C20-sphingosine); we found that these 2 types of gangliosides are differentially distributed in the mouse brain. While the C18-species was widely distributed throughout the frontal brain, the C20-species selectively localized along the entorhinal-hippocampus projections, especially in the molecular layer (ML) of the dentate gyrus (DG). We revealed development- and aging-related accumulation of the C-20 species in the ML-DG. Thus it is possible to consider that this brain-region specific regulation of LCB chain length is particularly important for the distinct function in cells of CNS

Recombinant "IMS TAG" proteins : a new method for validating bottom-up matrix-assisted laser desorption/ionisation ion mobility separation mass spectrometry imaging

Rationale - Matrix assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) provides a methodology to map the distribution of peptides generated by in situ tryptic digestion of biological tissue. It is challenging to correlate these peptides to the proteins from which they arise because of the many potentially overlapping and hence interfering peptide signals generated. Methods - A recombinant protein has been synthesised that when cleaved with trypsin yields a range of peptide standards for use as identification and quantification markers for multiple proteins in one MALDI-IMS-MSI experiment. Mass spectrometry images of the distribution of proteins in fresh frozen and formalin fixed paraffin embedded tissue samples following in situ tryptic digestion were generated by isolating signals on the basis of their m/z value and ion mobility drift time which were correlated to matching peptides in the recombinant standard. Results - Tryptic digestion of the IMS-TAG protein and MALDI-MS analysis yielded values for m/z and ion mobility drift time for the signature peptides included in it. MALDI-IMS-MSI images for the distribution of the proteins HSP 90 and Vimentin, in FFPE EMT6 mouse tumours and HSP-90 and Plectin in a fresh frozen mouse fibrosarcoma were generated by extracting ion images at the corresponding m/z and drift time from the tissue samples. Conclusions - The IMS-TAG approach provides a new means to confirm the identity of peptides generated by in situ digestion of biological tissue.</p

Detailed Structural Analysis of Lipids Directly on Tissue Specimens Using a MALDI-SpiralTOF-Reflectron TOF Mass Spectrometer

Direct tissue analysis using a novel tandem time-of-flight (TOF-TOF) mass spectrometer is described. This system consists of a matrix-assisted laser desorption/ionization ion source, a spiral ion trajectory TOF mass spectrometer “SpiralTOF (STOF)”, a collision cell, and an offset parabolic reflectron (RTOF). The features of this system are high precursor ion selectivity due to a 17-m flight path length in STOF and elimination of post-source decay (PSD) ions. The acceleration energy is 20 keV, so that high-energy collision-induced dissociation (HE-CID) is possible. Elimination of PSD ions allows observation of the product ions inherent to the HE-CID process. By using this tandem TOF instrument, the product ion spectrum of lipids provided detailed structural information of fatty acid residues