Development and prospects of dedicated tracers for the molecular imaging of bacterial infections

Bacterial infections have always been, and still are, a major global healthcare problem. For accurate treatment it is of utmost importance that the location(s), severity, type of bacteria, and therapeutic response can be accurately staged. Similar to the recent successes in oncology, tracers specific for molecular imaging of the disease may help advance the patient management. Chemical design and bacterial targeting mechanisms are the basis for the specificity of such tracers. The aim of this review is to provide a comprehensive overview of the molecular imaging tracers developed for optical and nuclear identification of bacteria and bacterial infections. Hereby we envision that such tracers can be used to diagnose infections and aid their clinical management. From these compounds we have set-out to identify promising targeting mechanisms and select the most promising candidates for further development.The Netherlands Organisation for Scientific Research (NWO; STW BGT 11272).http://pubs.acs.org/bchb201

U-SPECT-BioFluo: an integrated radionuclide, bioluminescence, and fluorescence imaging platform

Background: In vivo bioluminescence, fluorescence, and single-photon emission computed tomography (SPECT) imaging provide complementary information about biological processes. However, to date these signatures are evaluated separately on individual preclinical systems. In this paper, we introduce a fully integrated bioluminescence-fluorescence-SPECT platform. Next to an optimization in logistics and image fusion, this integration can help improve understanding of the optical imaging (OI) results. Methods: An OI module was developed for a preclinical SPECT system (U-SPECT, MILabs, Utrecht, the Netherlands). The applicability of the module for bioluminescence and fluorescence imaging was evaluated in both a phantom and in an in vivo setting using mice implanted with a 4 T1-luc + tumor. A combination of a fluorescent dye and radioactive moiety was used to directly relate the optical images of the module to the SPECT findings. Bioluminescence imaging (BLI) was compared to the localization of the fluorescence signal in the tumors. Results: Both the phantom and in vivo mouse studies showed that superficial fluorescence signals could be imaged accurately. The SPECT and bioluminescence images could be used to place the fluorescence findings in perspective, e.g. by showing tracer accumulation in non-target organs such as the liver and kidneys (SPECT) and giving a semi-quantitative read-out for tumor spread (bioluminescence). Conclusions: We developed a fully integrated multimodal platform that provides complementary registered imaging of bioluminescent, fluorescent, and SPECT signatures in a single scanning session with a single dose of anesthesia. In our view, integration of these modalities helps to improve data interpretation of optical findings in relation to radionuclide images

Use of a Single Hybrid Imaging Agent for Integration of Target Validation with In Vivo and Ex Vivo Imaging of Mouse Tumor Lesions Resembling Human DCIS

Screening of biomarker expression levels in tumor biopsy samples not only provides an assessment of prognostic and predictive factors, but may also be used for selection of biomarker-specific imaging strategies. To assess the feasibility of using a biopsy specimen for a personalized selection of an imaging agent, the chemokine receptor 4 (CXCR4) was used as a reference biomarker. Methods: A hybrid CXCR4 targeting peptide (MSAP-Ac-TZ14011) containing a fluorescent dye and a chelate for radioactive labeling was used to directly compare initial flow cytometry–based target validation in fresh tumor tissue to $in$ $vivo$ single photon emission computed tomography (SPECT) imaging and $in$ $vivo$ and $ex$ $vivo$ fluorescence imaging. Results: Flow cytometric analysis of mouse tumor derived cell suspensions enabled discrimination between 4T1 control tumor lesions (with low levels of CXCR4 expression) and CXCR4 positive early, intermediate and late stage MIN-O lesions based on their CXCR4 expression levels; CXCR4$^{basal}$, CXCR4$^+$ and CXCR4$^{++}$ cell populations could be accurately discriminated. Mean fluorescent intensity ratios between expression in MIN-O and 4T1 tissue found with flow cytometry were comparable to ratios obtained with in vivo SPECT/CT and fluorescence imaging, ex vivo fluorescence evaluation and standard immunohistochemistry. Conclusion: The hybrid nature of a targeting imaging agent like MSAP-Ac-TZ14011 enables integration of target selection, in vivo imaging and ex vivo validation using a single agent. The use of biopsy tissue for biomarker screening can readily be expanded to other targeting hybrid imaging agents and can possibly help increase the clinical applicability of tumor-specific imaging approaches

A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Plastic Embedded Gold Nanoparticles as 3D Printing Dichroic Nanocomposite Material

The incorporation of dichroic nanoparticles in 3D printable plastic results in a dichroic nanocomposite material that can be easily 3D printed. Gold nanoparticles that shows dichroic properties have been embedded in polyvinylalcohol, a standard 3D printable plastic. The nanocomposite shows dichroic properties and standard printability properties. </div

Gold nanoparticles embedded in a polymer as a 3D-printable dichroic nanocomposite material

Background: Nanotechnology, even if unknowingly, has been used for millennia. The occurrence of shiny colors in pottery and glass made hundreds and thousand of years ago is due to the presence of nanoparticles in the fabrication of such ornaments. In the last decade, 3D printing has revolutionized fabrication and manufacturing processes, making it easier to produce, in a simple and fast way, 3D objects. Results: In this paper we show how to fabricate a 3D-printable nanocomposite composed of dichroic gold nanoparticles and a 3D-printable polymer. The minute amount of gold nanoparticles used for obtaining the dichroic effect does not influence the mechanical properties of the polymer nor its printability. Thus, the nanocomposite can be easily 3D-printed using a standard 3D printer and shows a purple color in transmission and a brownish color in reflection. Conclusion: This methodology can be used not only by artists, but also for studying the optical properties of nanoparticles or, for example, for the 3D fabrication of optical filters.</p

On-Flow Immobilization of Polystyrene Microspheres on β-Cyclodextrin-Patterned Silica Surfaces through Supramolecular Host-Guest Interactions

Species-specific isolation of microsized entities such as microplastics and resistant bacteria from waste streams is becoming a growing environmental challenge. By studying the on-flow immobilization of micron-sized polystyrene particles onto functionalized silica surfaces, we ascertain if supramolecular host-guest chemistry in aqueous solutions can provide an alternative technology for water purification. Polystyrene particles were modified with different degrees of adamantane (guest) molecules, and silica surfaces were patterned with β-cyclodextrin (β-CD, host) through microcontact printing (μCP). The latter was exposed to solutions of these particles flowing at different speeds, allowing us to study the effect of flow rate and multivalency on particle binding to the surface. The obtained binding profile was correlated with Comsol simulations. We also observed that particle binding is directly aligned with particle's ability to form host-guest interactions with the β-CD-patterned surface, as particle binding to the functionalized glass surface increased with higher adamantane load on the polystyrene particle surface. Because of the noncovalent character of these interactions, immobilization is reversible and modified β-CD surfaces can be recycled, which provides a positive outlook for their incorporation in water purification systems.</p

Oxidant-responsive ferrocene-based cyclodextrin complex coacervate core micelles

Coacervate-core micelles are considered promising materials for several applications, from catalysis to drug delivery. However, oxidant-responsive coacervate-core micelles, able to undergo structural changes upon specific oxidation stimuli, are not well reported. Here, we present a novel ferrocene–dipicolinic acid derivative as redox-responsive subcomponent to be incorporated in cyclodextrin-based coacervate core micelles, C4Ms, with tuneable core structure and responsiveness towards H2O2 treatment. The Fc-C4Ms are formed combining three orthogonal supramolecular interactions, namely (i) metal-to-ligand coordination between europium(III) ions and dipicolinic acid molecules, (ii) host-guest interaction between beta cyclodextrins and ferrocenes and (iii) electrostatic coacervation interaction. The micelle stability against oxidation can be controlled by varying three main parameters: (a) the core-unit structure, from monomeric metal complexes to supramolecular oligomers, (b) the H2O2 equivalents and c) the ratio between redox-responsive and non-redox-responsive bislinker. The H2O2-responsive ferrocene-based systems might have an interesting application, e.g. reactive oxygen species-mediated drug delivery.</p