Versatile Bispidine-Based Bifunctional Chelators for 64 CuII -Labelling of Biomolecules.

Bifunctional chelators as parts of modular metal-based radiopharmaceuticals are responsible for stable complexation of the radiometal ion and for covalent linkage between the complex and the targeting vector. To avoid loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups. The C9 position of the very stable CuII chelator 3,7-diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisation does not disturb the metal binding centre. We describe the preparation and characterisation of a set of novel bispidine derivatives equipped with suitable functional groups for diverse bioconjugation reactions, including common amine coupling strategies (bispidine-isothiocyanate) and the Cu-free strain-promoted alkyne-azide cycloaddition. We demonstrate their functionality and versatility in an exemplary way by conjugation to an antibody-based biomolecule and validate the obtained conjugate in vitro and in vivo.

Biodistribution studies of ultrasmall silicon nanoparticles and carbon dots in experimental rats and tumor mice.

Ultrasmall clearable nanoparticles possess enormous potential as cancer imaging agents. In particular, biocompatible silicon nanoparticles (Si NPs) and carbon quantum dots (CQDs) hold great potential in this regard. Their facile surface functionalization easily allows the introduction of different labels for in vivo imaging. However, to date, a thorough biodistribution study by in vivo positron emission tomography (PET) and a comparative study of Si vs. C particles of similar size are missing. In this contribution, ultrasmall (size <5 nm) Si NPs and CQDs were synthesized and characterized by high-resolution transmission electron microscopy (HR-TEM), Fourier-transform infrared (FTIR), absorption and steady-state emission spectroscopy. Subsequent functionalization of NPs with a near-infrared dye (Kodak-XS-670) or a radiolabel (64Cu) enabled a detailed in vitro and in vivo study of the particles. For radiolabeling experiments, the bifunctional chelating agent S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to the amino surface groups of the respective NPs. Efficient radiolabeling of NOTA-functionalized NPs with the positron emitter 64Cu was found. The biodistribution and PET studies showed a rapid renal clearance from the in vivo systems for both variants of the nanoparticles. Interestingly, the different derivatives investigated exhibited significant differences in the biodistribution and pharmacokinetic properties. This can mostly be attributed to different surface charge and hydrophilicity of the NPs, arising from the synthetic strategy used to prepare the particles.

Identification and first insights into the structure and biosynthesis of chitin from the freshwater sponge Spongilla lacustris.

This work demonstrates that chitin is an important structural component within the skeletal fibers of the freshwater sponge Spongilla lacustris. Using a variety of analytical techniques ((13)C solid state NMR, FT-IR, Raman, NEXAFS, ESI-MS, Morgan-Elson assay and Calcofluor White Staining); we show that this sponge chitin is much closer to α-chitin, known to be present in other animals, than to ß-chitin. Genetic analysis confirmed the presence of chitin synthases, which are described for the first time in a sponge. The presence of chitin in both marine (demosponges and hexactinellids) and freshwater sponges indicates that this important structural biopolymer was already present in their common ancestor.

Optimization of pentadentate bispidines as bifunctional chelators for 64Cu positron emission tomography (PET).

Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

Mineralization of the metre-long biosilica structures of glass sponges is templated on hydroxylated collagen.

The minerals involved in the formation of metazoan skeletons principally comprise glassy silica, calcium phosphate or carbonate. Because of their ancient heritage, glass sponges (Hexactinellida) may shed light on fundamental questions such as molecular evolution, the unique chemistry and formation of the first skeletal silica-based structures, and the origin of multicellular animals. We have studied anchoring spicules from the metre-long stalk of the glass rope sponge (Hyalonema sieboldi; Porifera, Class Hexactinellida), which are remarkable for their size, durability, flexibility and optical properties. Using slow-alkali etching of biosilica, we isolated the organic fraction, which was revealed to be dominated by a hydroxylated fibrillar collagen that contains an unusual [Gly-3Hyp-4Hyp] motif. We speculate that this motif is predisposed for silica precipitation, and provides a novel template for biosilicification in nature.