Scientific Highlights from Research Division "Biology and Chemistry" (BIO)

BIO Scientific Highlights

Efficacy of a novel 177Lu-chCE7 radioimmunotherapeutic agent for disseminated ovarian cancer therapy

Research Division Biology and Chemistry (BIO), Center for Radiopharmaceutical Sciences,Tumor Targeting Group, Head Eliane Fischer. The L1-cell adhesion molecule is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1-CAM and exhibits anti-proliferative effects on L1-CAM-expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel 177Lu-chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth-inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl,an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10-tetraazacyclododecane-N-N′-N′-N‴-tetraacetic acid (DOTA) and labeled with the low-energy β-emitter 177Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 μg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of 177Lu-chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 ± 8.1% ID/g at 168 h postinjection. A single treatment with 177Lu-DOTA-chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted 177Lu-immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of 177Lu-DOTA-chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1-CAM.
Citation: E. Fischer, J. Grünberg, S. Cohrs, A. Hohn, K. Waldner-Knogler, S. Jeger, K. Zimmermann, I. Novak-Hofer and R. Schibli, International Journal of Cancer 130, 2715 (2012)

Publication: http://dx.doi.org/10.1002/ijc.26321

Further publications: ZRW Homepage

The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy

Research Division Biology and Chemistry (BIO), Radionuclicde Development Group, Head Konstantin Zhernosekov. The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents.
Citation: S. Lehenberger, C. Barkhausen, S. Cohrs, E. Fischer, J. Grünberg, A. Hohn, U. Köster, R. Schibli, A. Türler and K. Zhernosekov, Nuclear medicine and biology (2011)

Publication: http://dx.doi.org/10.1016/j.nucmedbio.2011.02.007

Further publications: LCH Homepage ZRW Homepage

10 March 2015

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Pb pollution from leaded gasoline in South America in the context of a 2000-year metallurgical history

Exploitation of the extensive polymetallic deposits of the Andean Altiplano in South America since precolonial times has caused substantial emissions of neurotoxic lead (Pb) into the atmosphere; however, its historical significance compared to recent Pb pollution from leaded gasoline is not yet resolved. We present a comprehensive Pb emission history for the last two millennia for South America, based on a continuous, high-resolution, ice core record from Illimani glacier. Illimani is the highest mountain of the eastern Bolivian Andes and is located at the northeastern margin of the Andean Altiplano.

30 January 2010

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The competition between organics and bromide at the aqueous solution – air interface as seen from ozone uptake kinetics and X-ray photoelectron spectroscopy

A more detailed understanding of the heterogeneous chemistry of halogenated species in the marine boundary layer is required. Here, we studied the reaction of ozone (O3) with NaBr solutions in presence and absence of citric acid (C6H8O7) under ambient conditions. Citric acid is used as a proxy for oxidized organic material present at the ocean surface or in sea spray aerosol.

The competition between organics and bromide at the aqueous solution – air interface as seen from ozone uptake kinetics and X-ray photoelectron spectroscopy

Research Division Biology and Chemistry (BIO), surface chemistry Group, Head Markus Ammann. A more detailed understanding of the heterogeneous chemistry of halogenated species in the marine boundary layer is required. Here, we studied the reaction of ozone (O3) with NaBr solutions in presence and absence of citric acid (C6H8O7) under ambient conditions. Citric acid is used as a proxy for oxidized organic material present at the ocean surface or in sea spray aerosol. On neat NaBr solutions, the observed kinetics is consistent with bulk reaction limited uptake, and a second order rate constant for the reaction of O3 + Br- is 57±10 M-1 s-1. On mixed NaBr citric acid aqueous solutions the uptake kinetics was faster than that predicted by bulk reaction limited uptake and also faster than expected based on an acid catalyzed mechanism. X-ray photoelectron spectroscopy (XPS) on a liquid microjet of the same solutions at 1.0 x 10^3 - 1.0 x 10^4 mbar was used to obtain quantitative insight into the interfacial composition relative to that of the bulk solutions. It revealed that bromide anion becomes depleted by 30±10 % while the sodium cation gets enhanced by 40±20 % at the aqueous solution-air interface of a 0.12 M NaBr solution mixed with 2.5 M citric acid in the bulk, attributed to the role of citric acid as a weak surfactant. Therefore, the enhanced reactivity of bromide solutions observed in presence of citric acid is not necessarily attributable to a surface reaction but could also result from an increased solubility of ozone at higher citric acid concentrations. Whether the acid catalyzed chemistry may have a larger effect on the surface than in the bulk to offset the effect of bromide depletion also remains open.
Citation: M.-T. Lee, M. A. Brown, S. Kato, A. Kleibert, A. Türler and M. Ammann, The Journal of Physical Chemistry A (2015)

Publication: http://dx.doi.org/10.1021/jp510707s

Further publications: LCH Homepage

13 May 2010

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The nature of nitrate at the ice surface

Trace contaminants such as strong acids have been suggested to affect the thickness of the quasi-liquid layer at the ice/air interface, which is at the heart of heterogeneous chemical reactions between snowpacks or cirrus clouds and the surrounding air. We used X-ray photoelectron spectroscopy (XPS) and electron yield near edge X-ray absorption fine structure (NEXAFS) spectroscopy at the Advanced Light Source (ALS) to probe the ice surface in the presence of HNO3 at 230 K.

The nature of nitrate at the ice surface

Surface Chemistry Research Group, Head Markus Ammann. Trace contaminants such as strong acids have been suggested to affect the thickness of the quasi-liquid layer at the ice/air interface, which is at the heart of heterogeneous chemical reactions between snowpacks or cirrus clouds and the surrounding air. We used X-ray photoelectron spectroscopy (XPS) and electron yield near edge X-ray absorption fine structure (NEXAFS) spectroscopy at the Advanced Light Source (ALS) to probe the ice surface in the presence of HNO3 at 230 K. We studied the nature of the adsorbed species at the ice/vapor interfaces as well as the effect of HNO3 on the hydrogen bonding environment at the ice surface. The NEXAFS spectrum of ice with adsorbed HNO3 can be represented as linear combination of the clean ice and nitrate solution spectrum, thus indicating that in the presence of HNO3 the ice surface consists of a mixture of clean ice and nitrate ions that are coordinated as in a concentrated solution at the same temperature but higher HNO3 pressures.
Citation: Křepelová, K., Newberg, J., Huthwelker, T., Bluhm, H., and Ammann, M. (2010). "The nature of nitrate at the ice surface studied by XPS and NEXAFS" Physical Chemistry Chemical Physics 12(31), 8870-8880.

Publication: http://dx.doi.org/10.1039/C0CP00359J

Further publications: LCH Homepage

Recent increase in black carbon concentrations
from a Mt. Everest ice core spanning 1860–2000 AD

Research Division Biology and Chemistry (BIO), Analytical Chemistry Group, Head Margit Schwikowski. A Mt. Everest ice core spanning 1860–2000 AD and analyzed at high resolution for black carbon (BC) using a Single Particle Soot Photometer demonstrates strong seasonality, with peak concentrations during the winter‐spring, and low concentrations during the summer monsoon season. BC concentrations from 1975–2000 relative to 1860–1975 have increased approximately threefold, indicating that BC from anthropogenic sources is being transported to high elevation regions of the Himalaya. The timing of the increase in BC is consistent with BC emission inventory data from South Asia and the Middle East, however since 1990 the ice core BC record does not indicate continually increasing BC concentrations. The Everest BC and dust records provide information about absorbing impurities that can contribute to glacier melt by reducing the albedo of snow and ice. There is no increasing trend in dust concentrations since 1860, and estimated surface radiative forcing due to BC in snow exceeds that of dust in snow. This suggests that a reduction in BC emissions may be an effective means to reduce the effect of absorbing impurities on snow albedo and melt, which affects Himalayan glaciers and the availability of water resources in major Asian rivers.
Citation: S.D. Kaspari, M. Schwikowski, M. Gysel, M.G. Flanner, S. Kang, S. Hou, and P.A. Mayewski, Geophysical Research Letters 38, L04703 (2011)

Publication: http://dx.doi.org/10.1029/2010GL046096

Further publications: LCH Homepage

18 February 2011

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Recent increase in black carbon concentrations
from a Mt. Everest ice core spanning 1860–2000 AD

A Mt. Everest ice core spanning 1860–2000 AD and analyzed at high resolution for black carbon (BC) using a Single Particle Soot Photometer demonstrates strong seasonality, with peak concentrations during the winter‐spring, and low concentrations during the summer monsoon season. BC concentrations from 1975–2000 relative to 1860–1975 have increased approximately threefold, indicating that BC from anthropogenic sources is being transported to high elevation regions of the Himalaya.

The role of long-lived reactive oxygen intermediates in the reaction of ozone with aerosol particles

Research Division Biology and Chemistry (BIO), Surface Chemistry Group, Head Markus Ammann. The heterogeneous reactions of ozone with aerosol particles are of central importance to air quality. They are studied extensively, but the molecular mechanisms and kinetics remain unresolved. Based on new experimental data and calculations, we show that long-lived reactive oxygen intermediates (ROIs) are formed. The chemical lifetime of these intermediates exceeds 100 seconds, which is much longer than the surface residence time of molecular ozone (~ ns). The ROIs explain and resolve apparent discrepancies between earlier quantum mechanical calculations and kinetic experiments. They play a key role in the chemical transformation and adverse health effects of toxic and allergenic air-particulate matter, such as soot, polycyclic aromatic hydrocarbons and proteins. ROIs may also be involved in the decomposition of ozone on mineral dust and in the formation and growth of secondary organic aerosols. Moreover, ROIs may contribute to the coupling of atmospheric and biospheric multiphase processes.
Citation: M. Shiraiwa, Y. Sosedova, A. Rouvière, H. Yang, Y. Zhang, J. P. D. Abbatt, M. Ammann and U. Pöschl, Nat Chem advance online publication, (2011)

Publication: http://dx.doi.org/10.1038/nchem.988

Further publications: LCH Homepage