Памяти Александра Евгеньевича Будникова

In photodynamic therapy (PDT), photosensitizers and light are used to cause photochemically induced cell death. The selectivity and the effectiveness of the phototoxicity in cancer can be increased by a specific uptake of the photosensitizer into tumor cells. A promising target for this goal is the folic acid receptor α (FRα), which is overexpressed on the surface of many tumor cells and mediates an endocytotic uptake. Here, we describe a polysaccharide-based nanoparticle system suitable for targeted uptake and its photochemical and photobiological characterization. The photosensitizer 5, 10, 15, 20-tetraphenyl-21H, 23H-porphyrine (TPP) was encapsulated in spermine- and acetal-modified dextran (SpAcDex) nanoparticles and conjugated with folic acid (FA) on the surface [SpAcDex(TPP)-FA]. The particles are successfully taken up by human HeLa-KB cells, and a light-induced cytotoxicity is observable. An excess of free folate as the competitor for the FRα-mediated uptake inhibits the phototoxicity. In conclusion, folate-modified SpAcDex particles are a promising drug delivery system for a tumor cell targeted photodynamic therapy

Distribution of infectious and parasitic agents among three sentinel bee species across European agricultural landscapes

Infectious and parasitic agents (IPAs) and their associated diseases are major environmental stressors that jeopardize bee health, both alone and in interaction with other stressors. Their impact on pollinator communities can be assessed by studying multiple sentinel bee species. Here, we analysed the field exposure of three sentinel managed bee species (Apis mellifera, Bombus terrestris and Osmia bicornis) to 11 IPAs (six RNA viruses, two bacteria, three microsporidia). The sentinel bees were deployed at 128 sites in eight European countries adjacent to either oilseed rape fields or apple orchards during crop bloom. Adult bees of each species were sampled before their placement and after crop bloom. The IPAs were detected and quantified using a harmonised, high-throughput and semi-automatized qPCR workflow. We describe differences among bee species in IPA profiles (richness, diversity, detection frequencies, loads and their change upon field exposure, and exposure risk), with no clear patterns related to the country or focal crop. Our results suggest that the most frequent IPAs in adult bees are more appropriate for assessing the bees' IPA exposure risk. We also report positive correlations of IPA loads supporting the potential IPA transmission among sentinels, suggesting careful consideration should be taken when introducing managed pollinators in ecologically sensitive environments

Protein-based nanoparticles for drug delivery applications

By the year 2030, the World Health Organization expects the total number of new cancer cases will grow to 21.7 million worldwide. Today, almost every seventh death is caused by cancer. Nanocarriers are very similar in size and shape to biological nanostructures and have already shown very promising results for drug delivery in cancer therapy. They increase drug solubility as well as bioavailability and reduce toxic side effects that often occur during chemotherapy as they selectively accumulate in the tumor tissue by an enhanced permeability and retention effect. Proteins show low toxicity and high biodegradability. Therefore, they can be a valuable source for highly defined biomaterials for the preparation of nanocarriers. In this work, a novel method for the preparation of nanoparticles based on the assembly of surface modified proteins that are soluble in organic solvents is presented. Particle preparation for hydrophobic payloads is carried out by an oil-in-water nanoemulsion technique without the need of additional cross-linking steps or denaturation for stabilization. The necessary lipophilic switch of the protein material is obtained by high surface PEGylation whilst preserving the native structure of the proteins. This system is first presented in detail for lysozyme, as model protein and doxorubicin as hydrophobic model drug. After a comprehensive analysis of the obtained protein-polymer conjugate, empty and doxorubicin-loaded nanoparticles are prepared with a diameter around 100 nm that still present the enzymatic activity of the native protein. The particles are stable in physiological buffers and a release of the therapeutic payload into cancer cells is only observed after a time dependent cellular uptake. Later, proteins in a broad range of molecular weights are used as starting material to exemplify that this preparation procedure has the potential to be transferred to any protein of choice. Here, also the influence of the polymer chain length on the solubility in organic solvents for the different protein sizes is presented. Additionally, the hydrophobic payload of the particles is exchanged by curcumin to present the high variability of this carrier system leading to particles with diameters below 200 nm. Furthermore, a water-in-oil-in-water nanoemulsion technique is used to prepare protein-based nanoparticles with an entrapped hydrophilic payload. This shows that the presented nanocarrier system has also high potential for the delivery of hydrophilic payloads, e.g. nucleic acids

Data confidentiality and reputation schemes in distributed information systems

Diese Arbeit betrachtet zwei anspruchsvolle Probleme aus dem Bereich Computer- und Kommunikationssicherheit und Vertrauen. Beim Datenbank-Serviceprovider-Problem moechte ein Anwender seine Datenbank an einen Datenbank-Serviceprovider (DSP) uebergeben, damit dieser sie betreiben und ihm zur Verfuegung stellen kann. Er vertraut diesem DSP, und damit auch vertraglichen Abmachungen, nur bedingt und muss die Vertraulichkeit seiner Daten durch technische Massnahmen sicherstellen. Das zweite Problem ist das Verbreiten verlaesslicher Reputationsinformation ueber eine (moeglicherweise sehr grosse) Anzahl von Netzwerk-Knoten in einer Peer-to-Peer-Umgebung (P2P). Beide Probleme straeuben sich hartnaeckig gegen einfache Loesungen. Im Gegensatz zu traditionellen Sicherheitsproblemen in der Informatik hat der Gegner in beiden ein hohes Mass an Kontrolle ueber die Situation. Der nicht ausreichend vertrauenswuerdige DSP muss in der Lage sein, die Daten seines Kunden zu verarbeiten, ohne etwas ueber sie zu lernen, was intuitiv wie ein Widerspruch erscheint. In P2P-Anwendungen ist es wuenschenswert, dass Knoten anonym beitreten und jederzeit wieder austreten koennen, aber diese Anonymitaet erleichtert es, falsche Reputationsinformation zu verbreiten. Ein Knoten, der erstmalig in ein P2P-Netzwerk eintritt, muss den behaupteten Beobachtungen anderer Knoten vertrauen. Die Resultate dieser Arbeit sind keine Idealloesungen, und dennoch aufschlussreich in mehrerlei Hinsicht: Es werden gelockerte, aber immer noch nuetzliche Sicherheitsbegriffe fuer das DSP-Problem vorgeschlagen; es werden theoretische Grenzen des DSP-Loesungsraums gezogen; und die Auswirkung feindseligen Verhaltens in P2P-Reputationssystemen wird durch heuristische Methoden reduziert. Ein Nebeneffekt unserer Arbeit ist ein speziell fuer Reputationssysteme in P2P-Netzwerken geeignetes Simulations-Tool, das zum Vergleich und zum Fine-Tuning bestehender und zukuenftiger Forschungsarbeiten genutzt werden kann.In this thesis we discuss two demanding problems from the field of computer and communication security that involve trust. The first is known as the database service provider problem: A database owner wants a database service provider (DSP) to host her database. She only trusts this DSP to a limited extent, so she does not want to rely solely on contractual solutions. It is therefore necessary to enforce confidentiality of her data by technical means. The second problem concerns a (potentially very large) number of network nodes in a peer-to-peer (P2P) environment. Both problems are notoriously hard because, other than in traditional computer security problems, the adversary has a lot of control over the situation. The untrusted DSP needs to be able to process the data without learning anything about it, which seems to be a contradiction. In P2P applications it is desirable that nodes can join anonymously, but anonymity makes it easy to spread false reputation information. A node that enters a P2P application network for the first time needs to trust the claimed observations of other nodes, independent of the rate of malicious behaviour. Our findings are not perfect solutions, but nevertheless instructive in several ways: We propose relaxed, but still practically useful, notions of security for the DSP problem; we identify theoretical limitations of the DSP solution space; and we gradually reduce the impact of adversarial behaviour in P2P reputation systems using heuristic methods. As a side effect of our work, we present a special-purpose framework for simulation of P2P reputation systems that can be used to compare and fine-tune previous and upcoming work

Nanoparticle Assembly of Surface-Modified Proteins

Nature’s biomaterials such as peptides and proteins represent a valuable source of highly defined macromolecules. Herein we developed a nanoparticle drug delivery system based on the assembly of surface-modified proteins that can be transferred into organic solvents and represent the structural material of the carrier system. The particles are prepared by an oil-in-water nanoemulsion technique without the need of additional denaturation or cross-linking steps for stabilization. We achieve the necessary lipophilic solubility switch of the protein material by high surface PEGylation under conservation of the native three-dimensional protein structure. This study focuses on lysozyme as model enzyme for the preparation of empty and doxorubicin-loaded nanoparticles with an average diameter of 100 nm. The particles are stable in physiological buffers and only release their therapeutic payload into cancer cells after a time-dependent cellular uptake. We also transferred this approach to various proteins, exemplifying the universal applicability of our new preparation method for protein-based nanoparticles

Zwischenbericht zum Forschungsprojekt 'Bedingungen der Verwendung paedagogischer Begleitforschungsergebnisse in der Praxis'

UuStB Koeln(38)-850106289 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Bedingungen der Verwendung paedagogischer Begleitforschungsergebnisse in der Praxis eine empirische Studie ; Abschlussbericht zum DFG-Forschungsprojekt

UuStB Koeln(38)-850106558 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman