Design and development of polynuclear ruthenium and platinum polypyridyl complexes in search of new anticancer agents

The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long and flexible linker. The complexes are characterized and have been studied for anticancer activity. The ruthenium unit of the dinuclear complexes varies in molecular structure, which may result in different interactions with DNA, the target of anticancer platinum and ruthenium antitumor compounds. The monofunctional ruthenium unit coordinates to the DNA-model base 9-ethylguanine. Variable temperature 1H NMR experiments prove that the base is hindered in its free rotation at room temperature. The crystal structure of a dinuclear ruthenium-platinum complex shows that the platinum unit is capable of intercalation and coordination (in)to DNA. Trinuclear and tetranuclear ruthenium and ruthenium-platinum complexes show higher activity than the dinuclear derivatives. A tetranuclear ruthenium complex displays interesting biological features. Human ovarian cisplatin sensitive carcinoma cells adhere together and form clots upon incubation of the complex. The effect possibly indicates antimetastatic activity. Dinuclear and trinuclear ruthenium-platinum complexes of short and semi-rigid linkers do not show significant activity against different cancer cell lines.Council for Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO). Financial support of COST Chemistry D20 for the stay in Brno is gratefully acknowledged.UBL - phd migration 201

[²¹²Pb]Pb-eSOMA-01:A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (212Pb) represents a promising avenue. A series of ligands based on octreotate was developed. Lead-203 was used as an imaging surrogate for the selection of the best candidate for the studies with lead-212. 203/212Pb radiolabeling and in vitro assays were carried out, followed by SPECT/CT imaging and ex vivo biodistribution in NCI-H69 tumor-bearing mice. High radiochemical yields (≥99%) and purity (≥96%) were obtained for all ligands. [203Pb]Pb-eSOMA-01 and [203Pb]Pb-eSOMA-02 showed high stability in PBS and mouse serum up to 24 h, whereas [203Pb]Pb-eSOMA-03 was unstable in those conditions. All compounds exhibited a nanomolar affinity (2.5–3.1 nM) for SSTR2. SPECT/CT images revealed high tumor uptake at 1, 4, and 24 h post-injection of [203Pb]Pb-eSOMA-01/02. Ex vivo biodistribution studies confirmed that the highest uptake in tumors was observed with [212Pb]Pb-eSOMA-01. [212Pb]Pb-eESOMA-01 displayed the highest absorbed dose in the tumor (35.49 Gy/MBq) and the lowest absorbed dose in the kidneys (121.73 Gy/MBq) among the three tested radioligands. [212Pb]Pb-eSOMA-01 is a promising candidate for targeted alpha therapy of NETs. Further investigations are required to confirm its potential.</p

The quality of task times: A methods research

IMAG-DLO is faced with large demands for labor data in spite of limited research capacity. Consequently IMAG-DLO is greatly concerned for the efficiency of the methodology used in task time synthesis, with even greater concern for maintaining the quality of the estimates of task times. Much effort has gone into determining the optimum method for collecting, computing, and storing labor data, the so-called task time synthesis. Task time synthesis can be achieved by four different procedures. These are, in order of decreasing accuracy, Predetermined time systems, Time study, Time registration, and Time estimation. These procedures are illustrated by a schematic overview and described. The applicability of the four procedures differs in horticulture depending on the research goals. The goals of labor management research focus on the evaluation of new developments in practice. Predetermined time systems are very time consuming and less suitable for the variable circumstances in horticulture. Time studies are most recommended as they appear to have the best price/quality relation for task time synthesis. Time registration delivers more indicative than normative task times, and Time estimation is very inaccurate and only to be applied when no other procedure is possible. Finally a protocol for this new direction in labor management research is described