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Aim: We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. Materials & methods: Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. Results: Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. Conclusion: TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy. Original submitted 6 November 2012; Revised submitted 25 March 2013

Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). We track nanocomplexes in vivo, examining the influence of HER2 antibody targeting on nanocomplex distribution over 72 h. This approach provides valuable, detailed information regarding the distribution and fate of complex nanoparticles designed for specific diagnostic and therapeutic functions.

Integrating multiple functionalities into individual nanoscale complexes is of tremendous importance in biomedicine, expanding the capabilities of nanoscale structures to perform multiple parallel tasks. Here, the ability to enhance two different imaging technologies simultaneously—fluorescence optical imaging and magnetic resonance imaging—with antibody targeting and photothermal therapeutic actuation is combined all within the same nanoshell-based complex. The nanocomplexes are constructed by coating a gold nanoshell with a silica epilayer doped with Fe 3 O 4 and the fluorophore ICG, which results in a high T 2 relaxivity (390mm ―1 s ―1 ) and 45× fluorescence enhancement of ICG. Bioconjugate nanocomplexes target HER2+ cells and induce photothermal cell death upon near-IR illumination.

Four out of six CYP enzymes involved in steroid biosynthesis are very interesting targets for the development of new drugs in order to treat a variety of severe illnesses. Herein we report on a novel approach for the discovery of hit compounds using new combinations of substructures of known CYP inhibitors. The synthesis of new scaffolds and their biological evaluation regarding inhibition of CYP17, CYP19, CYP11B1 and CYP11B2 are described. Thus, the very active (IC 50 = 114 and 100 nM) and selective (IC 50 >1000 nM) CYP11B2 inhibitors, compounds 4 and 5 , were obtained as well as the dual inhibitor 3 , reducing the activities of CYP19 and CYP11B2.

Regioselective C-C-bond formation reactions at 2,3-dibromobenzofuran (1) and 2,3,5-tribromobenzofuran (6) were studied. Pd-catalyzed Sonogashira and Negishi cross-coupling occurred with perfect regioselectivity at carbon atom C-2 to provide 2-substituted 3-bromobenzofurans (12, 14) and 3,5-dibromobenzofurans (17, 18) in 50-91% yield. A regioselective displacement of the bromine substituents in 3,5-dibromobenzofurans 18 was achieved by a halogen-metal exchange reaction at carbon atom C-3 and by a Ni-catalyzed Kumada cross-coupling at C-5. The methodology was applied to the synthesis of eupomatenoids 3, 4, 5, 6, and 15 (5). The synthesis of these compounds was achieved in overall yields of up to 60%.

Six different eupomatenoids ( 1a–c , 1f–h ) were prepared from 2,3,5-tribromobenzofuran ( 2 ) in a concise and high-yielding synthetic sequence. The overall yields vary between 29 and 60% over four to six steps. Key to the success of the syntheses is the high regioselectivity achieved in three Pd(0)- and Ni(0)-catalyzed cross-coupling reactions which were conducted consecutively. The order of substitution at the benzofuran nucleus is C-2, C-5 and C-3.

Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in ovarian cancer because of its participation in signaling pathway regulating cellular proliferation, differentiation, motility, and survival. Currently, effective diagnostic and therapeutic schemes are lacking for treating ovarian cancer, and consequently ovarian cancer has a high mortality rate. Although HER2 receptor expression does not usually affect the survival rates of ovarian cancer to the same extent as in breast cancer, it can be used as a docking site for directed nanotherapies in cases with de novo or acquired chemotherapy resistance. In this study, we have exploited a novel gold nanoshell–based complex (nanocomplex) for targeting, dual modal imaging, and photothermal therapy of HER2-overexpressing and drug-resistant ovarian cancer OVCAR3 cells in vitro. The nanocomplexes are engineered to simultaneously provide contrast as fluorescence optical imaging probe and a magnetic resonance imaging agent. Immunofluorescence staining and magnetic resonance imaging successfully show that nanocomplex–anti-HER2 conjugates specifically bind to OVCAR3 cells as opposed to the control, MDA-MB-231 cells, which have low HER2 expression. In addition, nanocomplexes targeted to OVCAR3 cells, when irradiated with near-IR laser, result in selective destruction of cancer cells through photothermal ablation. We also show that near-IR light therapy and the nanocomplexes by themselves are noncytotoxic in vitro. To the best of our knowledge, this is the first successful integration of dual modal bioimaging with photothermal cancer therapy for treatment of ovarian cancer. Based on their efficacy in vitro, these nanocomplexes are highly promising for image-guided photothermal therapy of ovarian cancer, as well as other HER2-overexpressing cancers. Mol Cancer Ther; 9(4); 1028–38. ©2010 AACR.

We investigate reflectance mode multi-frequency domain optical imaging with novel theranostic silica core gold nanostructures with Indocyanine Green. From phase sensitive images from homodyne measurements we determine optimal measurement parameters for nanoshell enhanced fluorescent dyes.

Multimodality molecular imaging is becoming more and more important to understand both the structural and the functional characteristics of tissue, organs and tumors. So far, invasive nuclear methods utilizing ionizing radiation have been the “gold standard” of molecular imaging. We investigate non-contact, non-invasive, patient-tolerant and inexpensive near infrared (NIR) frequency domain optical tomography (FDOT) as a functional complement to structural X-ray computed tomography (CT) data. We show a novel multifrequency NIR FDOT approach both in transmission and reflectance mode and employ radiative transport equation (RTE) for 3D reconstruction of a target with novel fluorescent gold nanoshell indocyanine green (NS ICG) in an ex vivo nude mouse. The results demonstrate that gold NS ICG with multifrequency NIR FDOT is a promising fluorophore for multimodal optical molecular image reconstruction.

Thirty-five novel substituted imidazolyl methylene biphenyls have been synthesized as CYP17 inhibitors for the potential treatment of prostate cancer. Their activities have been tested with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against CYP11B1, CYP11B2, and hepatic CYP enzymes 3A4, 1A2, 2B6 and 2D6. The core rigidified compounds (30-35) were the most active ones, being much more potent than Ketoconazole and reaching the activity of Abiraterone. However, they were not very selective. Another rather potent and more selective inhibitor (compound 23, IC(50)=345 nM) was further examined in rats regarding plasma testosterone levels and pharmacokinetic properties. Compared to the reference Abiraterone, 23 was more active in vivo, showed a longer plasma half-life (10h) and a higher bioavailability. Using our CYP17 homology protein model, docking studies with selected compounds were performed to study possible interactions between inhibitors and amino acid residues of the active site.

Excitation light leakage through fluorescence filters limits the sensitivity of fluorescence tomography. We demonstrate an image processing approach for suppressing the effects of excitation light leakage from NIR fluorescence images. Multiple excitation and fluorescence emission wavelength images of a fluorescence target buried in 1 % Liposyn solution were acquired by scanning an intensity modulated and line shaped NIR excitation source over the illumination/detection surface of the tissue phantom. Excitation images were used to identify the NIR source pattern and multiple global and local filters were designed to mitigate excitation light leakage in the fluorescence images. The image correction approaches were assessed by comparing the processed fluorescence images with the output of an adaptive finite element based photon diffusion model. The results show that localized error modeling based on the median reduces leakage effects by about 44 % compared to uncorrected data.

Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.

N-Carboxymethyl 3-hydroxypiperidine (6) undergoes substitution at C(6) via reductive cleavage of N,S-acetal 8a with lithium naphthalenide (LN) and trapping of the resulting carbanionic intermediate 9 with different electrophiles to give adducts 10. N,S-Acetal 8a also undergoes C-S homolysis and trapping of the resulting radical provides an alternative entry to 2-substituted-5-­hydroxypiperidines.

The use of drilling platforms for exploration drillings in ice-covered shallow water is expected to increase in the future. Jack-up platforms (JU) are regarded to be most suitable for exploration drillings due to their high mobility, their facile transportation and installation. Although having proved their capability for harsh environments, e.g. in the North Sea, jack-ups have neither been especially designed for nor have been operated frequently in icy waters. The problems associated with the operation of jack-ups in ice waters are related to structural integrity as well as to operational limitations. One objective of the research project MATRA-OSE was to check the design of JU for exploration and oil production in ice-covered, shallow-water areas. The global stability of JU as well as local and global loads acting on a three-legged jack-up drilling unit were investigated. The design loads were determined by analytical approaches. Different ice load cases were defined as the basis for the detail design. These load cases include local loads on single members of the platform legs like chords or braces as well as global loads, which may act on one individual leg or on several legs of the platform. Vertical forces, which result from a change of the water level (up-surge and down-surge) in case ice sheets are frozen to the platform legs were considered. Also the impact of ice being jammed between the platform legs was investigated. It has been found out that the most critical load case results from the ice being jammed between the platform legs. It should therefore be tried in practice to avoid the ice jamming by proper ice management, as the large ice loads calculated for this scenario may result in problems for the stability of a JU. Ice breakers could be used to pre break the ice and should try to clear the site from broken ice pieces before it starts to accumulate.Copyright © 2005 by ASME

Regioselective C-C-bond formation reactions at 2,3-dibromobenzofuran (1) and 2,3,5-tribromobenzofuran (6) were studied. Pd-catalyzed Sonogashira and Negishi cross-coupling occurred with perfect regioselectivity at carbon atom C-2 to provide 2-substituted 3-bromobenzofurans (12, 14) and 3,5-dibromobenzofurans (17, 18) in 50-91% yield. A regioselective displacement of the bromine substituents in 3,5-dibromobenzofurans 18 was achieved by a halogen-metal exchange reaction at carbon atom C-3 and by a Ni-catalyzed Kumada cross-coupling at C-5. The methodology was applied to the synthesis of eupomatenoids 3, 4, 5, 6, and 15 (5). The synthesis of these compounds was achieved in overall yields of up to 60%.

Six different eupomatenoids ( 1a–c , 1f–h ) were prepared from 2,3,5-tribromobenzofuran ( 2 ) in a concise and high-yielding synthetic sequence. The overall yields vary between 29 and 60% over four to six steps. Key to the success of the syntheses is the high regioselectivity achieved in three Pd(0)- and Ni(0)-catalyzed cross-coupling reactions which were conducted consecutively. The order of substitution at the benzofuran nucleus is C-2, C-5 and C-3.

Ice barriers installed in close vicinity to offshore platforms are designed to take the main loads resulting from floating ice by breaking the ice and piling-up the rubble ice. Platforms and equipment protected by ice barriers can be dimensioned considering only low ice loads and can thus be constructed more economically. Also, the safety of the platforms increases. One objective of the research project MATRA is to design suitable ice barriers for exploration and oil production in ice-covered, shallow-water areas. Several concepts were investigated, e.g. vertical and inclined piles as well as barges equipped with piles. Model tests were carried out under varying conditions in order to evaluate the design alternatives and to provide the design loads resulting from floating ice. The most suitable structure is a light-weight ice barrier with an inclined roof structure mounted on a barge which collects early, thin ice inside the structure, stabilizes itself by the piled-up rubble ice and by this later can withstand thicker ice. The measured loads were analysed and compared with loads theoretically derived from existing approaches. At the first stage, when the structure fills with ice, bending is the dominant failure mode. Once a rubble pile has built-up in front of the structure, other failure modes may become significant comprising buckling and crushing. The load-time curve shows a scattering behaviour and has very high load peaks of short duration, especially for thick ice. The analysis comprises a statistical evaluation of the loads, taking the site conditions in the Caspian Sea as reference. Design loads for different load-cases were derived, which are the basis for the stability analysis of the ice barrier. On the basis of the results of the stability analysis and considering the requirement that the structure shall be self-floating for transport, the structure was optimized and the detail design was carried out.Copyright © 2003 by ASME