Neli Koseva

Calcium chloride as co-catalyst of onium halides in the cycloaddition of carbon dioxide to oxiranes

The synthesis of 4-substituted 1,3-dioxolan-2-ones from the interaction between carbon dioxide and oxiranes in the presence of a catalytic system composed of tetraalkylammonium or phosphonium halide and calcium chloride has been investigated. It has been established that calcium chloride enhances the catalytic activity of the onium halides used. A mechanism describing the interaction between carbon dioxide and oxiranes has been suggested on the basis of the obtained experimental results. According to the assumed likely mechanism the catalytic system activates the oxirane and the opening of the oxirane ring is the rate-determining stage.

An information rich biomedical polymer library

We have designed and prepared a library of polymers with the aim to use a minimum number of polymers to obtain relevant information about structure–property correlations. An active ester homopolymer precursor and two blocked copolymer active ester precursor polymers were used to prepare a library of 16 cationic functionalised polymethacrylamides. These precursor polymers are narrow molecular weight distribution (MWD) polymers prepared by copper mediated polymerisation. This allows a precursor polymer to be used to generate a family of functionalised polymers for study, all with the same molecular weight characteristics. The polycations were then prepared by the sequential conjugation of two amines from the following set: (2-aminoethyl)trimethylammonium chloride hydrochloride (TMA), 3-(dimethylamino)propylamine (DMA), histamine (His) and 1-amino-2-propanol (AP). The conjugates contained different amounts of tertiary amine, quaternary ammonium, imidazole and hydroxypropyl pendent moieties that were selected to provide differing degrees of charge density along the polymer main chain. The molecular weight characteristics, viscosities and aqueous solubility of the polycations were evaluated at pH 4 and 7 to determine property trends. These conjugates were assessed for their ability to complex plasmid DNA at pH 7.4 and 4.5 by agarose gel electrophoresis. Triple detection GPC analysis at different pH values relevant to the cellular environment and photon correlation spectroscopy results indicated that some polycations formed interpolyelectrolyte complexes of under 100 nm. Preliminary titration and cellular biocompatibility studies are also described.

HPLC study on the stability of bendamustine hydrochloride immobilized onto polyphosphoesters.

Novel water soluble polymer complexes of bendamustine hydrochloride, a bifunctional alkylating agent with antimetabolic and cytotoxic activity, were developed using biodegradable polymer carriers-poly(oxyethylene H-phosphonate), poly(methyloxyethylene phosphate) and poly(hydroxyoxyethylene phosphate). Bendamustine hydrochloride was immobilized onto polyphosphoesters via covalent, ionic and hydrogen bonding. The structure of the complexes formed was elucidated by (1)H, (13)C, (31)P NMR and FT-IR spectroscopy. The chemical stability of bendamustine hydrochloride in the novel complexes was studied by HPLC analysis based on a validated method with appointed analytical parameters such as specificity, repeatability, limit of quantitation, limit of detection and linearity. The results from the HPLC indicate that in neutral (pH 7) and alkaline (pH 9) media bendamustine hydrochloride in the polymer complexes is more stable than the pure bendamustine hydrochloride. The enhanced stability of the immobilized drug is explained with the drug interaction with the polymer carriers or their degradation products.

Study on the Atherton–Todd reaction mechanism

A new mechanism of the Atherton–Todd reaction is discussed. The first step of the reaction between diesters of H-phosphonic acid and carbon tetrachloride in the presence of a base, commonly triethylamine, is a salt formation between carbon tetrachloride and the base [amine·Cl]+CCl3−. The trichloromethanide anion [CCl3−] deprotonates dialkyl H-phosphonate to form chloroform and dialkyl phosphonate anion [(RO)2P(O)]−. The latter anion reacts with the chlorine cation to furnish dialkyl chlorophosphate. Based on these findings the reaction has been applied for the oxidation of poly(alkylene H-phosphonate)s to the corresponding poly(alkylene chlorophosphate)s via the Atherton–Todd reaction.

Reversibly PEGylated nanocarrier for cisplatin delivery.

A star-shaped copolymer bearing a shell of poly(ethylene glycol) (PEG) chains was designed as a carrier of cisplatin. The proposed strategy was based on synthesis of a PEGylating agent and the incorporation of cisplatin as a reversible linker for PEG modification of the star macromolecules. The attachment of PEG chains to the stars and their release under physiological conditions, as well as the changes in particle size and mobility upon drug loading, was evidenced by diffusion ordered NMR spectroscopy (DOSY). The results demonstrated that PEGylation reduced inter-stars cross-linking and increased the stability of the nanocolloidal solution. The formation of PEG shell resulted in higher drug payload and improved drug release profile of the nanoconjugates. The in vitro bioassay in a panel of human tumor cell lines confirmed that the PEGylated conjugates exhibited superior growth inhibitory activity compared to the cisplatin-loaded nonPEGylated carrier.

Polyphosphoester conjugates of dinuclear platinum complex: synthesis and evaluation of cytotoxic and the proapoptotic activity.

Macromolecular conjugates of a dinuclear platinum complex with a spermidine bridge were synthesized using poly(oxyethylene H-phosphonate)s as precursor polymer. The complex species were attached to the polymer chain via a phosphoramide bond resulting from the reaction between the H-phosphonate groups and the middle amino group of the spermidine moiety. (1)H and (31)P{H} DOSY NMR spectral data were used to prove the conjugation reaction and to characterize the new species. The conjugates exhibited profound cytotoxicity in a panel of five chemosensitive human tumor cell lines and one cisplatin-resistant model (HL-60/CDDP), and were found to induce apoptotic cell death. A flow cytometric analysis encountered a cisplatin-dissimilar modulation of the cell cycle progression in KG-1 leukemic cells, following exposure to the dinuclear agents. Moreover, the novel compounds displayed less pronounced inhibitory activity against cultured murine renal epithelial cells, as compared to cisplatin.

Characterisation of different nanoparticles with a potential use for drug delivery in neuropsychiatric disorders

Abstract Objectives. Nanoparticles are promising tools for targeted delivery of drugs in the treatment of different diseases, including neuropsychiatric disorders. However, they need to be carefully characterised for any adverse effects which may occur in their presence. In this study, we evaluated the applicability of nanoparticles that belong to three different groups: (i) aggregates from amphiphilic diblock copolymers composed of poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-phenyl-2-oxazoline) (PPhOx) in different ratios, (ii) stabilised polymeric micelles (SPM) based on poly(ethylene oxide)-b-poly(propylene oxide)-bpoly(ethylene oxide) (PEO-PPO-PEO) and (iii) star-like polymer with poly(acrylic acid) arms and branched polystyrene interior (PSPAA). Methods. Using cultured human neural progenitor cells, we characterised six nanoparticles (POx-9, POx-23 and POx-46 – the polyoxazoline group, SPM-F38 and SPMMS – the SPM group, and PSPAA – the star-like polymer) for neurotoxicity and effect on neurodevelopmental genes. Nanoparticles ability to activate complement system in blood was assessed by ELISA. Results. None of the nanoparticles exhibited neurotoxicity. However, POx-9, POx-23, POx-46 and SPM-F38 activated complement system. POx-9 and SPM-F38 resulted in inhibition of expression of 19 and 26 out of 30 tested neurodevelopmental genes, respectively. Conclusions. Considering the properties of the studied nanoparticles, only PSPAA and SPMMS can be used at high concentrations for drug delivery without compromising neurogenesis and neurodevelopment, and activation of complement system.

Preparation of 4-hydroxy-methyl-1,3-dioxolan-2-one under phase transfer catalysis conditions

Abstract4-Hydroxymethyl-1,3-dioxolan-2-one has been prepared in 70% yield from 1-chloro-2,3-epoxypropane with alkali metal hydrogen carbonates under phase transfer catalysis conditions. Onium halides exhibit higher catalytic activity compared with that of tertiary amines or 18-crown-6.

Synthesis of aPHB-PEG Brush Co-polymers through ATRP in a Macroinitiator–Macromonomer Feed System and Their Characterization

A brush co-polymer composed of a biodegradable hydrophobic poly((R,S)-3-hydroxybutyrate) chain and biocompatible hydrophilic poly(ethylene glycol) brushes was designed as amphiphilic self-aggregating species with potential application in the health-care field. The co-polymer was prepared applying a three-step procedure: (i) ring-opening anionic polymerization of (R,S)-β-butyrolactone initiated by 2,2-bis(hydroxymethyl)butyric acid tetrabutyl ammonium salt yielding polyester with two hydroxyl functionalities at one chain terminus, (ii) synthesis of PHB-derived microinitiator species and (iii) ATRP of polyethylene glycol methyl ether methacrylate yielding an amphiphilic co-polymer. Chain structures and/or end-group functionalization were proven by 1H- and 13C-NMR spectroscopy of the products at each step of the synthetic procedure. The molecular weight and structure of the end-product were close to the expected values. The self-aggregation behavior of the brush co-polymer in an aqueous medium was evidenced by optical absorption probe technique and dynamic/static light scattering measurements.

Sonochemically born proteinaceous micro- and nanocapsules

The use of proteins as a substrate in the fabrication of micro- and nanoparticulate systems has attracted the interest of scientists, manufactures, and consumers. Albumin-derived particles were commercialized as contrast agents or anticancer therapeutics. Food proteins are widely used in formulated dietary products. The potential benefits of proteinaceous micro- and nanoparticles in a wide range of biomedical applications are indisputable. Protein-based particles are highly biocompatible and biodegradable structures that can impart bioadhesive properties or mediate particle uptake by specific interactions with the target cells. Currently, protein microparticles are engineered as vehicles for covalent attachment and/or encapsulation of bioactive compounds, contrast agents for magnetic resonance imaging, thermometric and oximetric imaging, sonography and optical coherence tomography, etc. Ultrasound irradiation is a versatile technique which is widely used in many and different fields as biology, biochemistry, dentistry, geography, geology, medicine, etc. It is generally recognized as an environmental friendly, cost-effective method which is easy to be scaled up. Currently, it is mainly applied for homogenization, drilling, cleaning, etc. in industry, as well for noninvasive scanning of the human body, treatment of muscle strains, dissolution of blood clots, and cancer therapy. Proteinaceous micro- and nanocapsules could be easily produced in a one-step process by applying ultrasound to an aqueous protein solution. The origin of this process is in the chemical changes, for example, sulfhydryl groups oxidation, that takes place as a result of acoustically generated cavitation. Partial denaturation of the protein most probably occurs which makes the hydrophobic interactions dominant and also responsible for the formation of stable capsules. This chapter aims to present the current state-of-the-art in the field of sonochemically produced protein micro- and nanocapsules, paying special attention to the proposed mechanisms for their formation, the factors that influence the capsules characteristics as well to the current applications of these particles. Current challenges in the field are also outlined as, for example, the ultrasound-protein interaction and other possible aspects of the mechanism of their formation.