The boreal landscape is complex mosaic of vast forests, lakes and wetlands. Through the landscape flows a fine network of streams and rivers, carrying dissolved and suspended material from atmospheric deposition and weathering of soils and bedrock to downstream recipients. This thesis investigates the transport of U, Th and other metals in the boreal landscape by comparing a set of catchments with contrasting characteristics, ranging from 0.12-68 km2 in area. Using uranium (234U/238U) and oxygen isotopes (δ18O) it was demonstrated that catchment size has a strong impact on the hydrological pathways and on the mobilisation of uranium. Both tracers also displayed a consistent shift towards more superficial sources and more superficial flow pathways when going from winter baseflow conditions to the spring flood. Large spatiotemporal variability was observed with U fluxes ranging from 1.7 -30 g km-2 a-1. Using a wide set of hydrochemical parameters and landscape characteristics it was demonstrated that wetlands play a decisive role for the biogeochemical cycling of many metals. Comparing normalised fluxes of 13 different elements (Al, Ba, Ca, Cr, Cu, La, Mg, Na, Ni, Si, Sr, U and Y) 73% of the spatial variance could be explained based on the wetland coverage and the affinity for organic matter, the latter of which was quantified using thermodynamic modelling. Hence, it was possible to link the large-scale transport patterns of a wide range of metals to fundamental biogeochemical properties. When restraining the analysis to the smaller streams (<10 km2), the explanatory power increased to 88%. For elements such as Na and Si with low affinity for organic matter the decrease in wetland-dominated catchments corresponded closely to the area of mineral soils that had been replaced by peat, indicating that reduced weathering was the main cause of the decrease. For organophilic metals the decrease in wetland-dominated catchments was even greater, suggesting that there also was an accumulation of these metals in the peat. This was confirmed by investigating the distribution of radionuclides in local mire, which revealed considerable accumulation of uranium and thorium along the edges of the mire. Based on the inventories of uranium and thorium and their distribution in the peat it was concluded that the mire historically had been a sink for these metals and that it most likely will continue to be so for a long time to come. All and all, wetlands were estimated to decrease the fluxes of metals from the boreal forests to downstream lakes and oceans by 20-40%, depending on how strongly they bind to organic matter.

As part of the radioactive exercises taking place around the world anthropogenic radionuclides were introduce to Puerto Rico’s terrestrial and aquatic environments beginning in 1962. Two major projects took place in the island, the Rain Forest Project and the construction of a Boiling Superheat Nuclear Power Plant (BONUS). While in operation several accidental shutdowns occurred at the BONUS facility. One of these accidental shutdowns released 582 MBq into the nearby environment. Vieques an island located few miles east of the main island has received anthropogenic inputs of heavy metals resulting from military practices conducted by the US Navy. Due to the potential presence of Cs-137 in soils and sediments in Puerto Rico a radiological assessment was performed. Downcore soil and sediment analysis as well as surface samples analysis was conduct in these three sites indicating the presence of Cs-137. Activity range varies among site from below detection limit to 12 dpm/g at Vieques, 15 dpm/g at Espiritu Santo Estuary and 12 dpm/g at the BONUS Facility. ICP-OES analysis indicates the existence of an oxic environment at the sedimentary system of the island. Cs-137 retention is strongly influenced by particle grain size and at the study sites clay was present in less than 20% for most sites. An X-ray diffraction analysis show that kaolinite and smectite are present at all sampling sites and illite is absent. To further analysis the ability of soil and sediments to retain adsorption and desorption was conducted using clay reference material and samples from the island. All samples, reference and natural, used in the study were placed in an aqueous solution that contained MES buffer (5.0 micromol, pKa of 6.1), ammonium nitrate (0.010 M) and the five metals (individual concentrations ranged from 0.48 micromol to 1.6 micromol). Solution pH was adjusted by titration with acid or base, depending on the nature of the sample. Results were quantified as distribution coefficients. These results indicate that the absorption and retention of Cs-137 in the sediments in Puerto Rico is driven by the mineralogy of the site.

Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases. Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF. When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab. Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.

Maisto radiologinio monitoringo, nustatant 90Sr ir 137Cs savituosius ir tūrinius aktyvumus, optimizavimo būdai nėra nagrinėti. Nenustatyta kaip maisto mėginių radiologinių tyrimų rezultatai atspindi radionuklidų kiekį visame suvartotame maiste. Šiuo metu negalima atsakyti į klausimą, ar šalies gyventojų apšvita dėl 90Sr ir 137Cs maiste jonizuojančiosios spinduliuotės, įvertinta pagal atliktų maisto radiologinių tyrimų rezultatus, buvo ir yra tikrai tokia, kokia buvo nustatyta ar nustatoma, t. y. trūksta duomenų apie tyrimų rezultatų reprezentatyvumą. Aplinkosauginiu ir ekonominiu požiūriu įvertinti maisto radiologinio monitoringo optimalumą bei parengti jo keitimui rekomendacijas dėl taršos aplinkoje lygių ir maisto produktų importo kaitos tendencijų yra aktualu, vengiant nepagrįstai didelių radiologinių tyrimų apimčių. Optimalus mėginių kiekis ir tinkamos mėginių rūšys įgalintų išvengti nepagrįstai didelės apšvitos gyventojams, tinkamai įvertinus vidutines dozes dėl maiste esančių 90Sr ir 137Cs jonizuojančiosios spinduliuotės. Maisto radiologinio monitoringo optimizavimas svarbus ir dėl pastarųjų metų tendencijų atskirose valstybėse, taip pat ir Lietuvoje, planuojant plėtoti branduolinę energetiką. Įvertinus naujų technologijų su jonizuojančiosios spinduliuotės šaltiniais plėtrą atskirose socialinėse ekonominėse srityse yra būtina optimali radiologinio monitoringo programa, garantuojanti gyventojų apsaugą nuo jonizuojančiosios spinduliuotės. / Optimization methods of radiological monitoring of food for the measurements of 90Sr and 137Cs activity concentrations are not estimated. No determination is made in which extent the results of measurements of activity concentration in the samples reflect the amount of radionuclides in all food consumed. The estimation of the ways for the optimization of radiological monitoring of food and preparation of recommendations for the changes in the monitoring program according the levels of radioactivity in the environment and amount of food imported is relevant for the optimization of measurement program not to extend the program and to save allocations. Optimization of food radiological monitoring program should help for the protection of the public to avoid exposure due to 90Sr and 137Cs in food when the average annual dose estimation is made correctly. Optimization of food radiological monitoring is important in nowadays when the planning of development of nuclear energy is going on in different countries including Lithuania. To take into account the development of new technologies using sources of ionizing radiation the optimization of food radiological monitoring program should assure the radiation protection of public.

This thesis is focused on the development, preclinical evaluation, and optimization of radiotracers for the detection of gastrin-releasing peptide receptor (GRPR)-expressing tumors. The work is divided into three distinct parts: (1) the development of bombesin (BN) antagonist (RM26)-based imaging radiotracers for the detection of GRPR-expressing tumors using different positron emission tomography (PET) and single photon emission computed tomography (SPECT) radionuclides (68Ga, 18F and 111In), (2) the establishment of a method to monitor the ligand-G protein-coupled receptor (GPCR) interaction in real time without requiring purification and stabilization of the receptors, and (3) the evaluation of radiopeptide structure-related factors (length of mini-PEG linker and composition of chelator for metal labeling) affecting the in vitro and in vivo characteristics of RM26-based tracers. We demonstrated the possibility of high-contrast in vivo imaging of GRPR-expressing xenografts despite the physiological expression of GRPR in abdominal organs. Fast radioactivity clearance from the blood and healthy organs, including receptor-positive organs, and long retention in the tumors resulted in high tumor-to-background ratios. A novel real-time assay for measuring the kinetics of the radiotracers targeting GPCR was evaluated. Living cells were used instead of purified receptors in this technology, bringing the developmental work one step closer to the true target environment (imaging in living systems). The comparative study of 68Ga-labeled NOTA-PEGn-RM26 with di-, tri-, tetra- and hexaethylene glycol chains demonstrated that the addition of only a few units of ethylene glycol to the spacer is insufficient to appreciably affect the biodistribution of the radiopeptide. Finally, a comparative study of 68Ga-labeled PEG2-RM26 analogs N-terminally conjugated to NOTA, NODAGA, DOTA or DOTAGA highlighted the influence of the chelator on the targeting properties of the radiopeptide. The main conclusion that can be drawn from this thesis is that 68Ga-NOTA-PEG2-RM26 has favorable biodistribution properties, such as rapid clearance from blood and tissues with physiological GRPR expression levels and long retention in GRPR-expressing tumors, and that this radiopeptide is potentially suitable for initial clinical investigation.

The objectives of this thesis are to produce radioactive antibody-conjugated gold nanoparticles to improve the efficacy of targeted radionuclide therapy for the treatment of cancer, and to demonstrate that this product can be produced at Texas A&M University. We have proposed a method for determining the distribution of radioactive nuclei per nanoparticle, which is critical for determining radiotherapeutic efficacy. Using the distribution of radioactive nuclei per nanoparticle, we have produced methods for calculating the radiative dose to tissue using nano-improved targeted radionuclide therapy, but more importantly we propose procedures to experimentally determine the efficacy of targeted radionuclide therapy improved by application of radioactive nanomaterials in combination with immunotherapy, nanomaterial cytotoxicity, and other cancer therapies such as chemotherapy. These methods can also be used to determine the efficacy of combinatory treatments as a function of time. Characterization of the antibody-nanoparticle attachment is critical; we have demonstrated successful antibody-nanoparticle conjugation using atomic force microscopy, dynamic light scattering, and agarose gel electrophoresis, providing more conclusive evidence of successful conjugation compared to flow cytometry. We provide a mathematical derivation from basic electron-transport principles which demonstrates the theoretical dosimetric advantages of applying radioactive nanomaterials to targeted radionuclide therapy. The general formulae can be applied to any tumor size, any radionuclide, and any pharmacokinetic nanoparticle distribution throughout the body, ultimately allowing a quick method of approximating the necessary activation time and treatment dosage parameters for a specific patient without burdensome Monte Carlo computational simulations. We further demonstrated that nano-TRT dosage to tumors should be considered as a function of radial position rather than average, as the dose across the tumor may be noticeably non-uniform causing some portions of the tumor to receive (potentially) significantly less dose than average.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 147-157).

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