Chemical Production and Microelectronic Applications of Graphene and Nano-Graphene Derivatives

Graphene and graphenic derivatives have rapidly emerged as an extremely promising system for electronic, optical, thermal, and electromechanical applications. Several approaches have been developed to produce these materials (i.e. scotch tape, CVD, chemical and solvent exfoliation). In this work we report a chemical approach to produce graphene by reducing graphene oxide (GO) via thermal or electrical methods. A morphological and electrical characterization of these systems has been performed using different techniques such as SPM, SEM, TEM, Raman and XPS. Moreover, we studied the interaction between graphene derivates and organic molecules focusing on the following aspects: - improvement of optical contrast of graphene on different substrates for rapid monolayer identification1 - supramolecular interaction with organic molecules (i.e. thiophene, pyrene etc.)4 - covalent functionalization with optically active molecules2 - preparation and characterization of organic/graphene Field Effect Transistors3-5 Graphene chemistry can potentially allow seamless integration of graphene technology in organic electronics devices to improve device performance and develop new applications for graphene-based materials. [1] E. Treossi, M. Melucci, A. Liscio, M. Gazzano, P. Samorì, and V. Palermo, J. Am. Chem. Soc., 2009, 131, 15576. [2] M. Melucci, E. Treossi, L. Ortolani, G. Giambastiani, V. Morandi, P. Klar, C. Casiraghi, P. Samorì, and V. Palermo, J. Mater. Chem., 2010, 20, 9052. [3] J.M. Mativetsky, E. Treossi, E. Orgiu, M. Melucci, G.P. Veronese, P. Samorì, and V. Palermo, J. Am. Chem. Soc., 2010, 132, 14130. [4] A. Liscio, G.P. Veronese, E. Treossi, F. Suriano, F. Rossella, V. Bellani, R. Rizzoli, P. Samorì and V. Palermo, J. Mater. Chem., 2011, 21, 2924. [5] J.M. Mativetsky, A. Liscio, E. Treossi, E. Orgiu, A. Zanelli, P. Samorì , V. Palermo, J. Am. Chem. Soc., 2011, 133, 14320

Development and performance assessment of a Plasma Focus electron beam generator for Intra-Operative Radiation Therapy

The Plasma Focus is a device designed to generate a plasma sheet between two coaxial electrodes by means of a high voltage difference. The plasma is then driven to collapse into a “pinch”, where thermonuclear conditions prevail. During the “pinch phase” charged particles are emitted, with two main components: an ion beam peaked forward and an electron beam directed backward. The electron beam emitted backward by Plasma Focus devices is being investigated as a radiation source for medical applications, using it to produce x-rays by interaction with appropriate targets (through bremsstrahlung and characteristic emission). A dedicated Plasma Focus device, named PFMA-3 (Plasma Focus for Medical Applications number 3), has been designed, put in operation and tested by the research groups of the Universities of Bologna and Ferrara. The very high dose rate (several gray per discharge, in less than 1 µs) is a peculiarity of this device that has to be investigated, as it might modify the relative biological effectiveness (RBE). Aim of this Ph.D. project was to investigate the main physical properties of the low-energy x-ray beams produced by a Plasma Focus device and their potential medical applications to IORT treatments. It was necessary to develop the optimal geometrical configuration; to evaluate the x-rays produced and their dose deposited; to estimate the energy electron spectrum produced in the “pinch phase”; to study an optimal target for the conversion of the x-rays; to conduct simulations to study the physics involved; and in order to evaluate the radio-biological features of the beam, cell holders had to be developed for both irradiations and cell growth conditions.

Soil application of Meliaceae derivatives: effect on carbon and nitrogen dynamics in the soil-plant system

The effect of soil incorporation of 7 Meliaceae derivatives (6 commercial neem cakes and leaves of Melia azedarach L.) on C and N dynamics and on nutrient availability to micropropagated GF677 rootstock was investigated. In a first laboratory incubation experiment the derivatives showed different N mineralization dynamics, generally well predicted by their C:N ratio and only partly by their initial N concentration. All derivatives increased microbial biomass C, thus representing a source of C for the soil microbial population. Soil addition of all neem cakes (8 g kg-1) and melia leaves (16 g kg-1) had a positive effect on plant growth and increased root N uptake and leaf green colour of micropropagated plants of GF677. In addition, the neem cakes characterized by higher nutrient concentration increased P and K concentration in shoot and leaves 68 days after the amendment. In another experiment, soil incorporation of 15N labeled melia leaves (16 g kg-1) had no effect on the total amount of plant N, however the percentage of melia derived-N of treated plants ranged between 0.8% and 34% during the experiment. At the end of the growing season, about 7% of N added as melia leaves was recovered in plant, while 70% of it was still present in soil. Real C mineralization and the priming effect induced by the addition of the derivatives were quantified by a natural 13C abundance method. The real C mineralization of the derivatives ranged between 22% and 40% of added-C. All the derivatives studied induced a positive priming effect and, 144 days after the amendment, the amount of C primed corresponded to 26% of added-C, for all the derivatives. Despite this substantial priming effect, the C balance of the soil, 144 days after the amendment, always resulted positive.

Regiocontrolled Synthesis of Pyrazole Derivatives Through 1,3-Dipolar Cycloaddition Reaction And Synthesis of Helicene-Thiourea based and Polymer Supported Soos's Catalyst for Asymmetric Synthesis

In first part we have developed a simple regiocontrolled protocol of 1,3-DC to get ring fused pyrazole derivatives. These pyrazole derivatives were synthesized using 1,3-DC between nitrile imine and various dipolarophiles such as alkynes, cyclic α,β-ketones, lactones, thiocatones and lactums. The reactions were found to be highly regiospecific. In second part we have discussed about helicene, its properties, synthesis and applications as asymmetric catalyst.Due to inherent chirality, herein we have made an attempt to synthesize the helicene-thiourea based catalyst for asymmetric catalysis. The synthesis involved formation of two key intermediates viz, bromo-phenanthrene 5 and a vinyl-naphthalene 10. The coupling of these two intermediates leads to formation of hexahelicene.

Grid Connected Doubly Fed Induction Generator Based Wind Turbine under LVRT

This project concentrates on the Low Voltage Ride Through (LVRT) capability of Doubly Fed Induction Generator (DFIG) wind turbine. The main attention in the project is, therefore, drawn to the control of the DFIG wind turbine and of its power converter and to the ability to protect itself without disconnection during grid faults. It provides also an overview on the interaction between variable speed DFIG wind turbines and the power system subjected to disturbances, such as short circuit faults. The dynamic model of DFIG wind turbine includes models for both mechanical components as well as for all electrical components, controllers and for the protection device of DFIG necessary during grid faults. The viewpoint of this project is to carry out different simulations to provide insight and understanding of the grid fault impact on both DFIG wind turbines and on the power system itself. The dynamic behavior of DFIG wind turbines during grid faults is simulated and assessed by using a transmission power system generic model developed and delivered by Transmission System Operator in the power system simulation toolbox Digsilent, Matlab/Simulink and PLECS.

Arbitrary Waveform Multilevel Generator for High Voltage High Frequency Plasma Actuators

This dissertation presents the theory and the conducted activity that lead to the construction of a high voltage high frequency arbitrary waveform voltage generator. The generator has been specifically designed to supply power to a wide range of plasma actuators. The system has been completely designed, manufactured and tested at the Department of Electrical, Electronic and Information Engineering of the University of Bologna. The generator structure is based on the single phase cascaded H-bridge multilevel topology and is comprised of 24 elementary units that are series connected in order to form the typical staircase output voltage waveform of a multilevel converter. The total number of voltage levels that can be produced by the generator is 49. Each level is 600 V making the output peak-to-peak voltage equal to 28.8 kV. The large number of levels provides high resolution with respect to the output voltage having thus the possibility to generate arbitrary waveforms. Maximum frequency of operation is 20 kHz. A study of the relevant literature shows that this is the first time that a cascaded multilevel converter of such dimensions has been constructed. Isolation and control challenges had to be solved for the realization of the system. The biggest problem of the current technology in power supplies for plasma actuators is load matching. Resonant converters are the most used power supplies and are seriously affected by this problem. The manufactured generator completely solves this issue providing consistent voltage output independently of the connected load. This fact is very important when executing tests and during the comparison of the results because all measures should be comparable and not dependent from matching issues. The use of the multilevel converter for power supplying a plasma actuator is a real technological breakthrough that has provided and will continue to provide very significant experimental results.

Activity and mechanisms of action of novel organosulfur derivatives of the HDAC inhibitor Valproic Acid in human experimental models of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) represents the leading cause of cancer death worldwide, and 5-year survival is about 16% for patients diagnosed with advanced lung cancer and about 70-90% when the disease is diagnosed and treated at earlier stages. Treatment of NSCLC is changed in the last years with the introduction of targeted agents, such as gefitinib and erlotinib, that have dramatically changed the natural history of NSCLC patients carrying specific mutations in the EGFR gene, or crizotinib, for patients with the EML4-ALK translocation. However, such patients represent only about 15-20% of all NSCLC patients, and for the remaining individuals conventional chemotherapy represents the standard choice yet, but response rate to thise type of treatment is only about 20%. Development of new drugs and new therapeutic approaches are so needed to improve patients outcome. In this project we aimed to analyse the antitumoral activity of two compounds with the ability to inhibit histone deacethylases (ACS 2 and ACS 33), derived from Valproic Acid and conjugated with H2S, in human cancer cell lines derived from NSCLC tissues. We showed that ACS 2 represents the more promising agent. It showed strong antitumoral and pro-apoptotic activities, by inducing membrane depolarization, cytocrome-c release and caspase 3 and 9 activation. It was able to reduce the invasive capacity of cells, through inhibition of metalloproteinases expression, and to induce a reduced chromatin condensation. This last characteristic is probably responsible for the observed high synergistic activity in combination with cisplatin. In conclusion our results highlight the potential role of the ACS 2 compound as new therapeutic option for NSCLC patients, especially in combination with cisplatin. If validated in in vivo models, this compound should be worthy for phase I clinical trials.

Cinchona alkaloids and BINOL derivatives as privileged catalysts or ligands in asymmetric synthesis

During the last fifteen years organocatalysis emerged as a powerful tool for the enantioselective functionalization of the most different organic molecules. Both C-C and C-heteroatom bonds can be formed in an enantioselective fashion using many types of catalyst and the field is always growing. Many kind of chiral catalysts have emerged as privileged, but among them Proline, cinchona alkaloids, BINOL, and their derivatives showed to be particularly useful chiral scaffolds. This thesis, after a short presentation of many organocatalysts and activation modes, focuses mainly on cinchona alkaloid derived primary amines and BINOL derived chiral Brønsted acids, describing their properties and applications. Then, in the experimental part, these compounds are used for the catalysis of new transformations. The enantioselective Friedel-Crafts alkylation of cyclic enones with naphthols using cinchona alkaloid derived primary amines as catalysts is presented and discussed. The results of this work were very good and this resulted also in a publication. The same catalysts are then used to accomplish the enantioselective addition of indoles to cyclic enones. Many catalysts in combination with many acids as co-catalysts were tried and the reaction was fully studied. Selective N-alkylation was obtained in many cases, in combination with quite good to good enantioselectivities. Also other kind of catalysis were tried for this reaction, with interesting results. Another aza-Michael reaction between OH-free hydroxylamines and nitrostyrene using cinchona alkaloid derived thioureas is briefly discussed. Then our attention focused on Brønsted acid catalyzed transformations. With this regard, the Prins cyclization, a reaction never accomplished in an enantioselective fashion until now, is presented and developed. The results obtained are promising. In the last part of this thesis the work carried out abroad is presented. In Prof. Rueping laboratories, an enantioselective Nazarov cyclization using cooperative catalysis and the enantioselective desymmetrization of meso-hydrobenzoin catalyzed by Brønsted acid were studied.

Development and evaluation of a 44 Ti, 44 Sc radionuclide generator and labeling of biomolecules with 44 Sc and 68 Ga for PET imaging

Non-invasive molecular-imaging technologies are playing a key role in drug discovery, development and delivery. Positron Emission Tomography (PET) is such a molecular imaging technology and a powerful tool for the observation of various deceases in vivo. However, it is limited by the availability of vectors with high selectivity to the target and radionuclides with a physical half-life which matches the biological half-life of the observed process. The 68Ge/68Ga radionuclide generator makes the PET-nuclide anywhere available without an on-site cyclotron. Besides the perfect availability 68Ga shows well suited nuclide properties for PET, but it has to be co-ordinated by a chelator to introduce it in a radiopharmaceuticals.rnHowever, the physical half-life of 68Ga (67.7 min) might limit the spectrum of clinical applications of 68Ga-labelled radiodiagnostics. Furthermore, 68Ga-labelled analogues of endoradiotherapeuticals of longer biological half-live such as 90Y- or 177Lu-labeled peptides and proteins cannot be used to determine individual radiation dosimetry directly. rnThus, radionuclide generator systems providing positron emitting daughters of extended physical half-life are of renewed interest. In this context, generator-derived positron emitters with longer physical half-life are needed, such as 72As (T½ = 26 h) from the 72Se/72As generator, or 44Sc (T½ = 3.97 h) from the 44Ti/44Sc generator.rnIn this thesis the implementation of radioactive gallium-68 and scandium-44 for molecular imaging and nuclear medical diagnosis, beginning with chemical separation and purification of 44Ti as a radionuclide mother, investigation of pilot generators with different elution mode, building a prototype generator, development and investigation of post-processing of the generator eluate, its concentration and further purification, the labeling chemistry under different conditions, in vitro and in vivo studies of labeled compounds and, finally, in vivo imaging experiments are described.

Structure, Dynamics and Reactivity in the Organic Solid State: Anthracene Derivatives and Charge Transfer Crystals

The work presented in this thesis tackles some important points concerning the collective properties of two typical categories of molecular crystals, i.e., anthracene derivatives and charge transfer crystals. Anthracene derivatives have constituted the class of materials from which systematical investigations of crystal-to-crystal photodimerization reactions started, developed and have been the subject of a new awakening in the recent years. In this work some of these compounds, namely, 9-cyanoanthacene, 9-anthacenecarboxylic acid and 9-methylanthracene, have been selected as model systems for a phenomenological approach to some key properties of the solid state, investigated by spectroscopic methods. The present results show that, on the basis of the solid state organization and the chemical nature of each compound, photo-reaction dynamics and kinetics display distinctive behaviors, which allows for a classification of the various processes in topochemical, non topochemical, reversible or topophysical. The second part of the thesis was focused on charge transfer crystals, binary systems formed by stoichiometric combinations of the charge donating perylene (D) and the charge accepting tetracyano-quinodimethane (A), this latter also in its fluorinated derivatives. The work was focused on the growth of single crystals, some of which not yet reported in the literature, by PVT technique. Structural and spectroscopic characterizations have been performed, with the aim of determining the degree of charge transfer between donor and acceptor in the co-crystals. An interesting outcome of the systematic search performed in this work is the definition of the experimental conditions which drive the crystal growth of the binary systems either towards the low (1:1) or the high ratio (3:1 or 3:2) stoichiometries.

Synthesis of new xanthene derivatives

Xanthene dyes, including fluorescein, are a well-known class of fluorescent dyes, which have widespread applications in natural sciences. The synthesis of xanthene derivatives via acid catalyzed condensation of substituted phenols with phthalic anhydride, to afford the asymmetric derivatives, is well established. The high temperature, harsh reaction conditions and often low yields make this method less convenient. The synthesis of xanthene dyes by direct modification of the fluorophore moiety is a great option to circumvent the above mentioned drawbacks. rnOur new synthetic strategy for the preparation of novel asymmetric xanthene dyes via direct conversion of hydroxyl groups on 3'- and 6'-positions into leaving groups by mesylation is reported. It was discovered that 3',6'-di-mesylated fluorescein underwent a nucleophilic aromatic substitution with sulfur nucleophiles and afforded new asymmetric xanthene sulfides. rnThe impact of substituents possessing an electron-withdrawing character such as chlorines and bromines was investigated with the aim to improve the aromatic substitution on the electron-rich fluorescein structure. It was observed that the incorporation of these groups did not considerably affect the substitution reaction and the yields were comparable with the unsubstituted fluorescein. rnThis strategy provided novel fluorescent probes with the linker suitable to further modifications. The modifications of the linker delivered fluorescein derivatives that could be used as fluorescent labels in peptides, oligonucleotides and for cell imaging. rnThe hydroxyl group on the linker was modified to achieve potent bioconjugate functionality such as azide. The new fluorescent azides were obtained in a 4-step synthesis, namely 2-(6-(2-azidoethylthio)-3-oxo-3H-xanthen-9-yl)benzoic acid with an overall yield of 13%, its 2',7'-dichloro derivative with an overall yield of 10% and its 2',4',5'-tribromo derivative with an overall yield of 1%, respectively. rnAn asymmetric xanthene sulfide with an amino functionality placed on the aliphatic linker, namely 2-(6-((2-aminoethyl)thio)-3-oxo-3H-xanthen-9-yl)benzoic acid, was obtained in a 3-step synthesis with an overall yield of 33%. rnThe impact of the substitution with sulfur nucleophiles on the 6'-position of the xanthene moiety on its fluorescent characteristics was investigated. In comparison with fluorescein new asymmetric xanthene sulfides afforded lower extinction coefficients and fluorescent quantum yields. On the other hand, the substitution with a sulfur nucleophile significantly improved the photostability of xanthene dyes. It was shown that after 10 hours of continuous excitation, the asymmetric sulfur-containing xanthene fluorophores exhibited 58-94% of their initial fluorescent intensities. This observation suggested that the novel dyes were 1-2 orders of magnitude more stable than fluorescein. rnThe azido-modified xanthenes were “clicked” via Cu(I)-catalyzed azide-alkyne cycloaddition with an oligonucleotide, which contained the terminal alkyne residue. rn

Liquid crystalline cellulose derivatives for mirrorless lasing

In this thesis cholesteric films made of liquid crystalline cellulose derivatives with improved optical properties were prepared. The choice of the solvent, hydrogen bond influencing additives, the synthetic realization of a very high degree of substitution on the cellulosic polymer and the use of mechanical stirring at the upper concentration limit of the liquid crystalline range were the basis for an improved alignment of the applied cellulose tricarbamates. In combination with a tuned substrate treatment and film preparation method, cholesteric films were obtained, with optical properties that were theoretically predicted and only known from low molecular weight liquid crystals so far. Subsequent polymerization allowed a permanent fixing of the alignment and the fabrication of free standing and insensitive films.rnThe incorporation of inorganic nanorods into the cholesteric host material was mediated with tailored block copolymers, available via controlled radical polymerization methods. In addition to the shape match between the rodlike mesogens of the host and the nanorods it was possible to increase the miscibility of both materials. Nevertheless, the size of the nanorods, in comparison to the mesogens, in these densely packed liquid crystalline phases as well as their long equilibration times were the reasons for phase separation. Nanorods are, in principle, valuable substitutes for organics, but their utilization in cellulosic CLC was not to be combined with a high quality alignment of the cholesteric structure.rnA swelling process of polymerized films in a dye solution or dissolving dyes in non-polymerized CLC was used for incorporation of the organic chromophores. With the first method the CLC could be aligned and polymerized without any disturbance due to dye molecules. The optical properties of dye and CLC were matched, with regard to mirrorless lasing devices. The dye was optically excited and laser emission supported by the cholesteric cavity was obtained. The polarization and wavelength of the emitted radiation as well as its bandwidth, the obtained interference pattern and threshold behavior of the emission proofed the feedback mechanism that was not believed to be realizable in liquid crystalline polymers. rnUtilization of a microfluidic co-flow injection device enabled us to transfer the properties of cellulosic CLC from the planar film shape to spherical micrometer sized particles. The pure material yielded particles with distorted mesogen alignment similar to films prepared by capillary flow. Dilution of the CLC with a solvent that migrated into the carrier phase during particle preparation provided the basis for particles with well ordered areas. rnAlthough cellulose derivatives were known for their liquid crystalline behavior for decades and synthesized in mass production, their application as feedback material was affected by bad optical properties. In comparison to low molar mass compounds, the low degree of order in the CLC phase was the cause. With the improved material, defined lasing emission was shown and characterized. Derivatives of cellulose are desirable materials, because, as a renewable resource, they are available in large amounts for a low price and need only simple derivatization reactions. The fabrication of CLC films with tunable lasing emission, for which this thesis can provide a starting point, is in good agreement with today's requirements of modern technology and its miniaturization.rn

Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new 18F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed 18F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable 18F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for 18F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K⊂2.2.2]+/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved.rnThe promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were conducted. The synthesis of the folate-boron clusters was straightforward. At first, a linker molecule based on maleic acid was synthesized, which was coupled to the boron cluster via Michael Addition of a thiol and alkene and subsequently coupled to the targeting moiety using CuAAC. The new conjugates of folate and boron clusters led to a significant increase of boron concentration in the cell of about 5-times compared to currently used and approved boron pharmaceuticals. rnMoreover, azido-folate derivatives were coupled to macromolecular carrier systems (pHPMA), which showed an enhanced and specific accumulation at target sites (up to 2.5-times) during in vivo experiments. A specific blockade could be observed up to 30% indicating an efficient targeting effect. A new kind of nanoparticles consisting of a PDLLA core and p((HPMA)-b-LMA)) as surfactants were developed and successfully radiolabeled via 18F-click chemistry in good RCYs of 8±3%rnThe nanoparticles were obtained via the miniemulsion technique in combination with solvent evaporation. The 18F-labeled nanoparticles were applied to in vivo testing using a mouse model. PET imaging showed a “mixed” biodistribution of low molecular weight as well as high molecular weight systems, indicating a partial loss of the 18F-labeled surfactant.rnIn conclusion, the presented work successfully utilized the FR-targeting concept in both, the diagnostic field (PET imaging) and for therapeutic approaches (BNCT, drug delivery systems). As a result, the high potential of FR-targeting in oncological applications has been shown and was confirmed by small animal PET imaging.rn

Synthese und Evaluierung makrozyklischer 68 Ga-MPI-Tracer auf Pyridaben-Basis

Herz-Kreislauf-Erkrankungen zählen weltweit zu den Hauptursachen, die zu frühzeitigem Tod führen. Pathophysiologisch liegt eine Gefäßwandverdickung durch Ablagerung arteriosklerotischer Plaques (Arteriosklerose) vor. Die molekulare Bildgebung mit den nuklearmedizinischen Verfahren SPECT und PET zielt darauf ab, minderperfundierte Myokardareale zu visualisieren, um den Krankheitsverlauf durch frühzeitige Therapie abschwächen zu können. Routinemäßig eingesetzt werden die SPECT-Perfusionstracer [99mTc]Sestamibi und [99mTc]Tetrofosmin. Zum Goldstandard für die Quantifizierung der Myokardperfusion werden allerdings die PET-Tracer [13N]NH3 und [15O]H2O, da eine absolute Bestimmung des Blutflusses in mL/min/g sowohl in der Ruhe als auch bei Belastung möglich ist. 2007 wurde [18F]Flurpiridaz als neuer Myokardtracer vorgestellt, dessen Bindung an den MC I sowohl in Ratten, Hasen, Primaten als auch in ersten klinischen Humanstudien eine selektive Myokardaufnahme zeigte. Um eine Verfügbarkeit des Radionuklids über einen Radionuklidgenerator gewährleisten zu können, sollten makrozyklische 68Ga-Myokard-Perfusionstracer auf Pyridaben-Basis synthetisiert und evaluiert werden. Die neue Tracer-Klasse setzte sich aus dem makrozyklischen Chelator, einem Linker und dem Insektizid Pyridaben als Targeting-Vektor zusammen. Struktur-Affinitätsbeziehungen konnten auf Grund von Variation des Linkers (Länge und Polarität), der Komplexladung (neutral und einfach positiv geladen), des Chelators (DOTA, NODAGA, DO2A) sowie durch einen Multivalenzansatz (Monomer und Dimer) aufgestellt werden. Insgesamt wurden 16 neue Verbindungen synthetisiert. Ihre 68Ga-Markierung wurde hinsichtlich pH-Wert, Temperatur, Vorläufermenge und Reaktionszeit optimiert. Die DOTA/NODAGA-Pyridaben-Derivate ließen sich mit niedrigen Substanzmengen (6 - 25 nmol) in 0,1 M HEPES-Puffer (pH 3,4) bei 95°C innerhalb 15 min mit Ausbeuten > 95 % markieren. Für die DO2A-basierenden Verbindungen bedurfte es einer mikrowellengestützen Markierung (300 W, 1 min, 150°C), um vergleichbare Ausbeuten zu erzielen. Die in vitro-Stabilitätstests aller Verbindungen erfolgten in EtOH, NaCl und humanem Serum. Es konnten keine Instabilitäten innerhalb 80 min bei 37°C festgestellt werden. Unter Verwendung der „shake flask“-Methode wurden die Lipophilien (log D = -1,90 – 1,91) anhand des Verteilungs-quotienten in Octanol/PBS-Puffer ermittelt. Die kalten Referenzsubstanzen wurden mit GaCl3 hergestellt und zur Bestimmung der IC50-Werte (34,1 µM – 1 µM) in vitro auf ihre Affinität zum MC I getestet. In vivo-Evaluierungen erfolgten mit den zwei potentesten Verbindungen [68Ga]VN160.MZ und [68Ga]VN167.MZ durch µ-PET-Aufnahmen (n=3) in gesunden Ratten über 60 min. Um die Organverteilung ermitteln zu können, wurden ex vivo-Biodistributionsstudien (n=3) vorgenommen. Sowohl die µ-PET-Untersuchungen als auch die Biodistributionsstudien zeigten, dass es bei [68Ga]VN167.MZ zwar zu einer Herzaufnahme kam, die jedoch eher perfusionsabhängig ist. Eine Retention des Tracers im Myokard konnte in geringem Umfang festgestellt werden.

Radiomarkierung von HPMA-basierten, funktionalisierten Polymeren mit metallischen Radionukliden für die medizinische Anwendung als Theranostika

Für eine erfolgreiche Behandlung bösartiger Tumore ist eine frühzeitige Diagnose, aber auch eine effektive und effiziente Therapie essentiell. In diesem Zusammenhang sind Nanomaterialien in den Fokus der Arzneimittelentwicklung gerückt, welche für Diagnostik und Therapie genutzt werden könnten.rnSystematische Studien zur Radiometallmarkierung von Nanopartikeln und deren Stabilität in vitro im Zusammenhang mit der Struktur des Linkers und dem Anteil an Chelator wurden anhand verschiedener HPMA-DOTA-Konjugate durchgeführt. Es konnte gezeigt werden, dass die Linkerstruktur und der Belegungsgrad sowohl die Markierung als auch die in vitro -Stabilität von radiometallmarkierten HPMA-rnDOTA-Konjugaten beeinflussen.rnFür die Markierung selbst stehen mehrere Generator-produzierte metallische Positronenemitter zur Verfügung. Infolge der gesetzlichen Bestimmungen muss das Eluat der Generatoren bestimmte Spezifikationen (Elutionsausbeute, Durchbruch des Mutternuklids, Gehalt an Fremdionen, pH-Wert etc.) erfüllen, um für die Darstellung von Radiopharmaka verwendet werden zu können.rnFür das bereits etablierte PET-Nuklid 68Ga konnte eine Ethanol-basierte Aufreinigung entwickelt werden, welche hohe Elutions- und Markierungsausbeuten sowie Radionuklidreinheit garantiert und damit einen wichtigen Schritt für die Entwicklung von Kit-Formulierungen repräsentiert. Ausserdem konnten zwei Methoden zur Qualitätskontrolle entwickelt werden, welche es ermöglichen die Radionuklidreinheit des initialen 68Ga-Eluats, aber auch des finalen 68Ga-Radiopharmakons innerhalb einer Stunde ohne γ–Spektroskopie zu bestimmen.rnWährend mit 68Ga die Pharmakokinetik markierter Derivate für einen Zeitraum von bis 3 Stunden zugänglich ist, deckt das Generator-produzierte 44Sc eine Periode von bis zu einem Tag ab. Damit lässt sich die Pharmakokinetik markierter polymerer Drug Carrier-Systeme – von der frühen Ausscheidungsphase bis hin zu organspezifischen Akkumulationen durch passives und aktives Targeting – gut beschreiben.rnFür 44Sc konnte anhand der Modellverbindung DOTATOC gezeigt werden, dass das aufgereinigte Generatoreluat für die Markierung mit hohen radiochemischen Ausbeuten geeignet ist und etablierte Markierungsmethoden übertragbar sind. In weiterführenden Studien zur molekularen Bildgebung könnte das Potential dieses PET-Nuklids für die Langzeitbildgebung gezeigt werden.