From defined polymer architectures to structure-property relationships in vivo

Makromolekulare Wirkstoffträgersysteme sind von starkem Interesse bezüglich der klinischen Anwendung chemotherapeutischer Agenzien. Um ihr klinisches Potential zu untersuchen ist es von besonderer Bedeutung das pharmakokinetische Profil in vivo zu bestimmen. Jede Veränderung der Polymerstruktur beeinflusst die Körperverteilung des entsprechenden Makromoleküls. Aufgrund dessen benötigt man detailliertes Wissen über Struktur-Eigenschaftsbeziehungen im lebenden Organismus, um das Nanocarrier System für zukünftige Anwendungen einzustellen. In dieser Beziehung stellt das präklinische Screening mittels radioaktiver Markierung und Positronen-Emissions-Tomographie eine nützliche Methode für schnelle sowie quantitative Beobachtung von Wirkstoffträgerkandidaten dar. Insbesondere poly(HPMA) und PEG sind im Arbeitsgebiet Polymer-basierter Therapeutika stark verbreitet und von ihnen abgeleitete Strukturen könnten neue Generationen in diesem Forschungsbereich bieten.rnDie vorliegende Arbeit beschreibt die erfolgreiche Synthese verschiedener HPMA und PEG basierter Polymer-Architekturen – Homopolymere, Statistische und Block copolymere – die mittels RAFT und Reaktivesterchemie durchgeführt wurde. Des Weiteren wurden die genannten Polymere mit Fluor-18 und Iod-131 radioaktiv markiert und mit Hilfe von microPET und ex vivo Biodistributionsstudien in tumortragenden Ratten biologisch evaluiert. Die Variation in Polymer-Architektur und darauffolgende Analyse in vivo resultierte in wichtige Schlussfolgerungen. Das hydrophile / lipophile Gleichgewicht hatte einen bedeutenden Einfluss auf das pharmakokinetische Profil, mit besten in vivo Eigenschaften (geringe Aufnahme in Leber und Milz sowie verlängerte Blutzirkulationszeit) für statistische HPMA-LMA copolymere mit steigendem hydrophoben Anteil. Außerdem zeigten Langzeitstudien mit Iod-131 eine verstärkte Retention von hochmolekularen, HPMA basierten statistischen Copolymeren im Tumorgewebe. Diese Beobachtung bestätigte den bekannten EPR-Effekt. Hinzukommend stellen Überstrukturbildung und damit Polymergröße Schlüsselfaktoren für effizientes Tumor-Targeting dar, da Polymerstrukturen über 200 nm in Durchmesser schnell vom MPS erkannt und vom Blutkreislauf eliminiert werden. Aufgrund dessen wurden die hier synthetisierten HPMA Block copolymere mit PEG Seitengruppen chemisch modifiziert, um eine Verminderung in Größe sowie eine Reduktion in Blutausscheidung zu induzieren. Dieser Ansatz führte zu einer erhöhten Tumoranreicherung im Walker 256 Karzinom Modell. Generell wird die Körperverteilung von HPMA und PEG basierten Polymeren stark durch die Polymer-Architektur sowie das Molekulargewicht beeinflusst. Außerdem hängt ihre Effizienz hinsichtlich Tumorbehandlung deutlich von den individuellen Charakteristika des einzelnen Tumors ab. Aufgrund dieser Beobachtungen betont die hier vorgestellte Dissertation die Notwendigkeit einer detaillierten Polymer-Charakterisierung, kombiniert mit präklinischem Screening, um polymere Wirkstoffträgersysteme für individualisierte Patienten-Therapie in der Zukunft maßzuschneidern.rn

Multifunctional polyether architectures : versatile materials for surface attachment and functionalization

Chapter 1 of this thesis comprises a review of polyether polyamines, i.e., combinations of polyether scaffolds with polymers bearing multiple amino moieties. Focus is laid on controlled or living polymerization methods. Furthermore, fields in which the combination of cationic, complexing, and pH-sensitive properties of the polyamines and biocompatibility and water-solubility of polyethers promise enormous potential are presented. Applications include stimuli-responsive polymers with a lower critical solution temperature (LCST) and/or the ability to gel, preparation of shell cross-linked (SCL) micelles, gene transfection, and surface functionalization.rnIn Chapter 2, multiaminofunctional polyethers relying on the class of glycidyl amine comonomers for anionic ring-opening polymerization (AROP) are presented. In Chapter 2.1, N,N-diethyl glycidyl amine (DEGA) is introduced for copolymerization with ethylene oxide (EO). Copolymer microstructure is assessed using online 1H NMR kinetics, 13C NMR triad sequence analysis, and differential scanning calorimetry (DSC). The concurrent copolymerization of EO and DEGA is found to result in macromolecules with a gradient structure. The LCSTs of the resulting copolymers can be tailored by adjusting DEGA fraction or pH value of the environment. Quaternization of the amino moieties by methylation results in polyelectrolytes. Block copolymers are used for PEGylated gold nanoparticle formation. Chapter 2.2 deals with a glycidyl amine monomer with a removable protecting group at the amino moiety, for liberation of primary amines at the polyether backbone, which is N,N-diallyl glycidyl amine (DAGA). Its allyl groups are able to withstand the harsh basic conditions of AROP, but can be cleaved homogeneously after polymerization. Gradient as well as block copolymers poly(ethylene glycol)-PDAGA (PEG-PDAGA) are obtained. They are analyzed regarding their microstructure, LCST behavior, and cleavage of the protecting groups. rnChapter 3 describes applications of multi(amino)functional polyethers for functionalization of inorganic surfaces. In Chapter 3.1, they are combined with an acetal-protected catechol initiator, leading to well-defined PEG and heteromultifunctional PEG analogues. After deprotection, multifunctional PEG ligands capable of attaching to a variety of metal oxide surfaces are obtained. In a cooperative project with the Department of Inorganic and Analytical Chemistry, JGU Mainz, their potential is demonstrated on MnO nanoparticles, which are promising candidates as T1 contrast agents in magnetic resonance imaging. The MnO nanoparticles are solubilized in aqueous solution upon ligand exchange. In Chapter 3.2, a concept for passivation and functionalization of glass surfaces towards gold nanorods is developed. Quaternized mPEG-b-PqDEGA diblock copolymers are attached to negatively charged glass surfaces via the cationic PqDEGA blocks. The PEG blocks are able to suppress gold nanorod adsorption on the glass in the flow cell, analyzed by dark field microscopy.rnChapter 4 highlights a straightforward approach to poly(ethylene glycol) macrocycles. Starting from commercially available bishydroxy-PEG, cyclic polymers are available by perallylation and ring-closing metathesis in presence of Grubbs’ catalyst. Purification of cyclic PEG is carried out using α-cyclodextrin. This cyclic sugar derivative forms inclusion complexes with remaining unreacted linear PEG in aqueous solution. Simple filtration leads to pure macrocycles, as evidenced by SEC and MALDI-ToF mass spectrometry. Cyclic polymers from biocompatible precursors are interesting materials regarding their increased blood circulation time compared to their linear counterparts.rnIn the Appendix, A.1, a study of the temperature-dependent water-solubility of polyether copolymers is presented. Macroscopic cloud points, determined by turbidimetry, are compared with microscopic aggregation phenomena, monitored by continuous wave electron paramagnetic resonance (CW EPR) spectroscopy in presence of the amphiphilic spin probe and model drug (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). These thermoresponsive polymers are promising candidates for molecular transport applications. The same techniques are applied in Chapter A.2 to explore the pH-dependence of the cloud points of PEG-PDEGA copolymers in further detail. It is shown that the introduction of amino moieties at the PEG backbone allows for precise manipulation of complex phase transition modes. In Chapter A.3, multi-hydroxyfunctional polysilanes are presented. They are obtained via copolymerization of the acetal-protected dichloro(isopropylidene glyceryl propyl ether)methylsilane monomer. The hydroxyl groups are liberated through acidic work-up, yielding versatile access to new multifunctional polysilanes.

From anionic polymerization in continuous flow to macromolecular architectures and stimuli-responsive surfaces

The thesis can be divided in four parts and summarized as follows:(i) The investigation and development of a continuous flow synthesis procedure affording end-functional polymers by anionic polymerization and subsequent termination in one reaction step and on a multigram scale was carried out. Furthermore, the implementation of not only a single hydroxyl but multiple orthogonal functionalities at the chain terminus was achieved by utilizing individually designed, functional epoxide-based end-capping reagents.(ii) In an additional step, the respective polymers were used as macroinitiators to prepare in-chain functionalized block copolymers and star polymers bearing intriguing novel structural and material properties. Thus, the second part of this thesis presents the utilization of end-functional polymers as precursors for the synthesis of amphiphilic complex and in some cases unprecedented macromolecular architectures, such as miktoarm star polymers based on poly(vinyl pyridine), poly(vinyl ferrocene) and PEO.(iii) Based on these structures, the third part of this thesis represents a detailed investigation of the preparation of stimuli-responsive ultrathin polymer films, using amphiphilic junction point-reactive block copolymers. The single functionality at the block interface can be employed as anchor group for the covalent attachment on surfaces. Furthermore, the change of surface properties was studied by applying different external stimuli.(iv) An additional topic related to the oxyanionic polymerizations carried out in the context of this thesis was the investigation of viscoelastic properties of different hyperbranched polyethers, inspired by the recent and intense research activities in the field of biomedical applications of multi-functional hyperbranched materials.

Caratterizzazione e progettazione di un sistema di comunicazione con ultra low power long range transceiver

Lo sviluppo di nuove tecnologie sempre più innovative e all’avanguardia ha portato ad un processo di costante rivisitazione e miglioramento di sistemi tecnologici già esistenti. L’esempio di Internet risulta, a questo proposito, interessante da analizzare: strumento quotidiano ormai diventato alla portata di tutti, il suo processo di rivisitazione ha portato allo sviluppo dell’Internet Of Things (IoT), neologismo utilizzato per descrivere l'estensione di Internet a tutto ciò che può essere trasformato in un sistema elettronico, controllato attraverso la rete mondiale che oggi può essere facilmente fruibile grazie all’utilizzo di Smartphone sempre più performanti. Lo scopo di questa grande trasformazione è quello di creare una rete ad-hoc (non necessariamente con un accesso diretto alla rete internet tramite protocolli wired o wireless standard) al fine di stabilire un maggior controllo ed una maggiore sicurezza, alla quale è possibile interfacciare oggetti dotati di opportuni sensori di diverso tipo, in maniera tale da condividere dati e ricevere comandi da un operatore esterno. Un possibile scenario applicativo della tecnologia IoT, è il campo dell'efficienza energetica e degli Smart Meter. La possibilità di modificare i vecchi contatori del gas e dell’acqua, tutt’oggi funzionanti grazie ad una tecnologia che possiamo definire obsoleta, trasformandoli in opportuni sistemi di metring che hanno la capacità di trasmettere alla centrale le letture o i dati del cliente, di eseguire operazioni di chiusura e di apertura del servizio, nonché operazioni sulla valutazione dei consumi, permetterebbe al cliente di avere sotto controllo i consumi giornalieri. Per costruire il sistema di comunicazione si è utilizzato il modem Semtech SX1276, che oltre ad essere low-power, possiede due caratteristiche rivoluzionarie e all’avanguardia: utilizza una modulazione del segnale da trasmettere innovativa e una grande capacità di rilevare segnali immersi in forti fonti di rumore ; la possibilità di utilizzare due frequenze di trasmissione diverse, 169 MHz e 868MHz.

Iron(III)-Pivalate-Based Complexes with Tetranuclear {Fe-4(mu(3)-O)(2)}(8+) Cores and N-Donor Ligands: Formation of Cluster and Polymeric Architectures

Different synthetic routes have been used for the preparation of a new tetranuclear [Fe4O2(O2CCMe3)(8)(bpm)] cluster (1) and a one-dimensional coordination polymer [Fe4O2-(O2CCMe3)(8)(hmta)](n) (2) (bpm = 2,2'-bipyrimidine and hmta = hexamethylenetetramine). For cluster 1, two structural isomers, 1a and 1b center dot 3MeCN, have been found. X-ray crystallographic analysis showed that all complexes consist of a central {Fe-4(mu(3)-O)(2)}(8+) core. In 1a, metal ions in the core are additionally linked by six bridging pivalates as two other pivalates and a bpm ligand are chelated to Fe-III ions, whereas in cluster 1b, metal ions in the {Fe-4(mu(3)-O)(2)}(8+) core are linked by seven bridging pivalates and only one carboxylate as well as bpm are chelated to the iron centers. In coordination polymer 2, [Fe4O2(O2CCMe3)(8)] clusters are bridged by hmta ligands to form zigzag chains. Magnetic measurements have been carried out to characterize these complexes and revealed antiferromagnetic interactions between Fe-III ions with best-fit parameters of J(wb) = -72.2 (1a) and -88.7 cm(-1) (1b) for wing...body interactions.

AGENT BASED, DISTRIBUTED CONTROL STRATEGIES AND OPTIMIZATION OF PLUG-IN ELECTRIC VEHICLES ON SMART/MICROGRID ARCHITECTURES

This thesis will present strategies for the use of plug-in electric vehicles on smart and microgrids. MATLAB is used as the design tool for all models and simulations. First, a scenario will be explored using the dispatchable loads of electric vehicles to stabilize a microgrid with a high penetration of renewable power generation. Grid components for a microgrid with 50% photovoltaic solar production will be sized through an optimization routine to maintain storage system, load, and vehicle states over a 24-hour period. The findings of this portion are that the dispatchable loads can be used to guard against unpredictable losses in renewable generation output. Second, the use of distributed control strategies for the charging of electric vehicles utilizing an agent-based approach on a smart grid will be studied. The vehicles are regarded as additional loads to a primary forecasted load and use information transfer with the grid to make their charging decisions. Three lightweight control strategies and their effects on the power grid will be presented. The findings are that the charging behavior and peak loads on the grid can be reduced through the use of distributed control strategies.

The Meta in Meta-object Architectures

Behavioral reflection is crucial to support for example functional upgrades, on-the-fly debugging, or monitoring critical applications. However the use of reflective features can lead to severe problems due to infinite metacall recursion even in simple cases. This is especially a problem when reflecting on core language features since there is a high chance that such features are used to implement the reflective behavior itself. In this paper we analyze the problem of infinite meta-object call recursion and solve it by providing a first class representation of meta-level execution: at any point in the execution of a system it can be determined if we are operating on a meta-level or base level so that we can prevent infinite recursion. We present how meta-level execution can be represented by a meta-context and how reflection becomes context-aware. Our solution makes it possible to freely apply behavioral reflection even on system classes: the meta-context brings stability to behavioral reflection. We validate the concept with a robust implementation and we present benchmarks.

High depth-resolution laser ablation chemical analysis of additive-assisted Cu electroplating for microchip architectures

Laser ablation/ionisation mass spectrometry with a vertical resolution at a nanometre scale was applied for the quantitative characterisation of the chemical composition of additive-assisted Cu electroplated deposits used in the microchip industry. The detailed chemical analysis complements information gathered by optical techniques and allows new insights into the metal deposition process.

Domain-Specific Multi-Modeling of Security Concerns in Service-Oriented Architectures

As a common reference for many in-development standards and execution frameworks, special attention is being paid to Service-Oriented Architectures. SOAs modeling, however, is an area in which a consensus has not being achieved. Currently, standardization organizations are defining proposals to offer a solution to this problem. Nevertheless, until very recently, non-functional aspects of services have not been considered for standardization processes. In particular, there exists a lack of a design solution that permits an independent development of the functional and non-functional concerns of SOAs, allowing that each concern be addressed in a convenient manner in early stages of the development, in a way that could guarantee the quality of this type of systems. This paper, leveraging on previous work, presents an approach to integrate security-related non-functional aspects (such as confidentiality, integrity, and access control) in the development of services.

Multi Domain-Specific Modeling of the Security Concerns of Service-Oriented Architectures

Service-Oriented Architectures (SOA), and Web Services (WS), the technology generally used to implement them, achieve the integration of heterogeneous technologies, providing interoperability, and yielding the reutilization of pre-existent systems. Model-driven development methodologies provide inherent benefits such as increased productivity, greater reuse, and better maintainability, to name a few. Efforts on achieving model-driven development of SOAs already exist, but there is currently no standard solution that addresses non-functional aspects of these services as well. This paper presents an approach to integrate these non-functional aspects in the development of web services, with an emphasis on security.

Distributed models in P-Systems architectures to reduce computation time

Membrane systems are computational equivalent to Turing machines. However, their distributed and massively parallel nature obtains polynomial solutions opposite to traditional non-polynomial ones. At this point, it is very important to develop dedicated hardware and software implementations exploiting those two membrane systems features. Dealing with distributed implementations of P systems, the bottleneck communication problem has arisen. When the number of membranes grows up, the network gets congested. The purpose of distributed architectures is to reach a compromise between the massively parallel character of the system and the needed evolution step time to transit from one configuration of the system to the next one, solving the bottleneck communication problem. The goal of this paper is twofold. Firstly, to survey in a systematic and uniform way the main results regarding the way membranes can be placed on processors in order to get a software/hardware simulation of P-Systems in a distributed environment. Secondly, we improve some results about the membrane dissolution problem, prove that it is connected, and discuss the possibility of simulating this property in the distributed model. All this yields an improvement in the system parallelism implementation since it gets an increment of the parallelism of the external communication among processors. Proposed ideas improve previous architectures to tackle the communication bottleneck problem, such as reduction of the total time of an evolution step, increase of the number of membranes that could run on a processor and reduction of the number of processors.

Membrane Dissolution in Distributed Architectures of P-Systems

The goal of this paper is twofold. Firstly, to survey in a systematic and uniform way the main results regarding the way membranes can be placed on processors in order to get a software/hardware simulation of P-Systems in a distributed environment. Secondly, we improve some results about the membrane dissolution problem, prove that it is connected, and discuss the possibility of simulating this property in the distributed model. All this yields an improvement in the system parallelism implementation since it gets an increment of the parallelism of the external communication among processors. Also, the number of processors grows in such a way that is notorious the increment of the parallelism in the application of the evolution rules and the internal communica-tionsstudy because it gets an increment of the parallelism in the application of the evolution rules and the internal communications. Proposed ideas improve previous architectures to tackle the communication bottleneck problem, such as reduction of the total time of an evolution step, increase of the number of membranes that could run on a processor and reduction of the number of processors

Radiofrequency architectures and technologies for software defined radio

Six-port network is an interesting radiofrequency architecture with multiple possibilities. Since it was firstly introduced in the seventies as an alternative network analyzer, the six-port network has been used for many applications, such as homodyne receivers, radar systems, direction of arrival estimation, UWB (Ultra-Wide-Band), or MIMO (Multiple Input Multiple Output) systems. Currently, it is considered as a one of the best candidates to implement a Software Defined Radio (SDR). This thesis comprises an exhaustive study of this promising architecture, where its fundamentals and the state-of-the-art are also included. In addition, the design and development of a SDR 0.3-6 GHz six-port receiver prototype is presented in this thesis, which is implemented in conventional technology. The system is experimentally characterized and validated for RF signal demodulation with good performance. The analysis of the six-port architecture is complemented by a theoretical and experimental comparison with other radiofrequency architectures suitable for SDR. Some novel contributions are introduced in the present thesis. Such novelties are in the direction of the highly topical issues on six-port technique: development and optimization of real-time I-Q regeneration techniques for multiport networks; and search of new techniques and technologies to contribute to the miniaturization of the six-port architecture. In particular, the novel contributions of this thesis can be summarized as: - Introduction of a new real-time auto-calibration method for multiport receivers, particularly suitable for broadband designs and high data rate applications. - Introduction of a new direct baseband I-Q regeneration technique for five-port receivers. - Contribution to the miniaturization of six-port receivers by the use of the multilayer LTCC (Low Temperature Cofired Ceramic) technology. Implementation of a compact (30x30x1.25 mm) broadband (0.3-6 GHz) six-port receiver in LTTC technology. The results and conclusions derived from this thesis have been satisfactory, and quite fruitful in terms of publications. A total of fourteen works have been published, considering international journals and conferences, and national conferences. Aditionally, a paper has been submitted to an internationally recognized journal, which is currently under review.

Pipelined Radix- 2k Feedforward FFT Architectures

The appearance of radix-$2^{2}$ was a milestone in the design of pipelined FFT hardware architectures. Later, radix-$2^{2}$ was extended to radix-$2^{k}$ . However, radix-$2^{k}$ was only proposed for single-path delay feedback (SDF) architectures, but not for feedforward ones, also called multi-path delay commutator (MDC). This paper presents the radix-$2^{k}$ feedforward (MDC) FFT architectures. In feedforward architectures radix-$2^{k}$ can be used for any number of parallel samples which is a power of two. Furthermore, both decimation in frequency (DIF) and decimation in time (DIT) decompositions can be used. In addition to this, the designs can achieve very high throughputs, which makes them suitable for the most demanding applications. Indeed, the proposed radix-$2^{k}$ feedforward architectures require fewer hardware resources than parallel feedback ones, also called multi-path delay feedback (MDF), when several samples in parallel must be processed. As a result, the proposed radix-$2^{k}$ feedforward architectures not only offer an attractive solution for current applications, but also open up a new research line on feedforward structures.