Juraj Kronek

New hyperbranched poly(ether amide)s via nucleophilic ring opening of 2-oxazoline-containing monomers

An AB 2 monomer containing one oxazoline and two phenolic units was synthesized. The polymerization of the monomer 2-(3,5-dihydroxyphenyl)-1,3-oxazoline in N-methylcaprolactam resulted in a well-defined and fully soluble, high molar mass, hyperbranched polymer with etheramide structure. The hydrolysis of some oxazoline groups as side reaction limits the achieved molar mass when the polymerization is carried out in tetramethylene sulfone or in bulk. The polymers were characterized by one (1D) and two (2D) dimensional 1 H and 13 C NMR spectroscopy which allowed to determine the degree of branching to be 50% as expected from statistics. DSC and TGA measurements revealed a glass transition temperature of 176°C and a decomposition onset of 330°C. The thermal ring-opening reaction was studied in situ by DSC measurements.

Synthesis and bioimmunological efficiency of poly(2-oxazolines) containing a free amino group

Novel amphiphilic copolymers on the basis of 2-oxazolines containing a free amino group were prepared. The copolymers were synthesized by the living cationic polymerization of 2-ethyl-2-oxazoline (ETOX) and 2-(4-aminophenyl)-2-oxazoline (APOX). The main goal of this work was the synthesis of water soluble polymer material with the defined number of functional groups necessary for the attachment of proteins and polysaccharides. A high concentration of free amino groups allows immobilization of various biosubstances, e.g. drugs, proteins or polysaccharides. Thermal properties have been studied with respect to the composition of the copolymers. Cytotoxicity and the bioimmunological efficiency of the selected copolymer were studied.

Immunomodulatory efficiency of poly(2-oxazolines)

Poly(2-oxazolines) represent promising polymer materials for biomedical applications. The activation of mouse lymphoid macrophage line P388.D1 (clone 3124) by two selected representatives of poly(2-oxazolines), namely poly(2-ethyl-2-oxazoline) (PETOX100) and poly[2-(4-aminophenyl)-2-oxazoline-co-2-ethyl-2-oxazoline] (AEOX10), was assessed in vitro. The immunomodulatory efficacy of both polymers was evaluated via the induced release of pro-inflammatory cytokines (TNF-α, IL-1α and IL-6) and the acceleration of reactive free radicals. The present study revealed effective structure-immunomodulating associations of AEOX10 and PETOX100, which are desirable in biomedical and pharmaceutical applications of aliphatic and aromatic poly (2-oxazolines) in vivo.

Preparation of synthetic polyoxazoline based carrier and Vibrio cholerae O-specific polysaccharide conjugate vaccine.

Multiple chemical attachments of carbohydrate antigens to linear polymer represent promising technique for creating biologically effective conjugates. A novel conjugate consisting of detoxified lipopolysaccharide of Vibrio cholerae O135, linear polymer (polyoxazoline copolymer, serving as a matrix) and BSA (as immunogenic protein), has been prepared. The reaction conditions were optimized for obtaining high degree of conjugation. Analytical methods were evaluated to characterize conjugates obtained. Proposed chemistry is suitable for preparation of multivalent glycoconjugates in general.

Azo-group labelled polyesters by end-capping with 2-oxazoline derivatives - preparation

Two azobenzene containing 2-oxazolines were used for labelling of polyesters with carboxylic end groups by the end-capping method. The reaction proceeded under the conditions of reactive processing, and in a solution. High conversions in melt were achieved in several minutes. The coupling of the modifiers was proved by NMR spectroscopy.

Azo‐group labelled polyesters by end‐capping with 2‐oxazoline derivatives – photochemical properties

Two azobenzene containing 2-oxazolines were used for labeling of a polyester with carboxylic end groups by the end-capping method. The modification was performed under the conditions of either reactive processing or in a solution. Photochemical activity of the prepared polymers, as well as that of the modifiers was studied. The polymers prepared represent new photosensitive materials that undergo photochemical trans-cis isomerizations and reverse cis-trans reactions.

Delayed adverse effects of neonatal exposure to polymeric nanoparticle poly(ethylene glycol)-block-polylactide methyl ether on hypothalamic-pituitary-ovarian axis development and function in Wistar rats.

We studied delayed effects of neonatal exposure to polymeric nanoparticle poly(ethylene glycol)-block-polylactide methyl ether (PEG-b-PLA) on the endpoints related to pubertal development and reproductive function in female Wistar rats from postnatal day 4 (PND4) to PND 176. Female pups were injected intraperitoneally, daily, from PND4 to PND7 with PEG-b-PLA (20 or 40mg/kg b.w.). Both doses of PEG-b-PLA accelerated the onset of vaginal opening compared with the control group. In the low-dose PEG-b-PLA-treated group, a significantly reduced number of regular estrous cycles, increased pituitary weight due to hyperemia, vascular dilatation and congestion, altered course of hypothalamic gonadotropin-releasing hormone-stimulated luteinizing hormone secretion, and increased progesterone serum levels were observed. The obtained data indicate that neonatal exposure to PEG-b-PLA might affect the development and function of hypothalamic-pituitary-ovarian axis (HPO), and thereby alter functions of the reproductive system in adult female rats. Our study indicates a possible neuroendocrine disrupting effect of PEG-b-PLA nanoparticles.

Ex Vivo and In Vitro Studies on the Cytotoxicity and Immunomodulative Properties of Poly(2-isopropenyl-2-oxazoline) as a New Type of Biomedical Polymer

Poly(2-alkenyl-2-oxazoline)s are promising functional polymers for a variety of biomedical applications, such as drug delivery systems, peptide conjugates, or gene delivery. In this study, poly(2-isopropenyl-2-oxazoline) (PIPOx) is prepared through free-radical polymerization initiated with azobisisobutyronitrile. Reactive 2-oxazoline units in the side chain support an addition reaction with different compounds containing a carboxylic group, which facilitates the preparation of polymers labeled with two different fluorescent dyes. The cytotoxicities of 2-oxazoline monomers, PIPOx, and fluorescently labeled PIPOx are evaluated in vitro using an 3-(4,5-Dimethyldiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and ex vivo using a cell proliferation assay with adenosine triphosphate bioluminescence. The cell uptake of labeled PIPOx is used to determine the colocalization of PIPOx with cell organelles that are part of the endocytic pathway. For the first time, it is shown that poly(2-isopropenyl-2-oxazoline) is a biocompatible material and is suitable for biomedical applications; further, its immunomodulative properties are evaluated.

Synthesis and Polymerization Reactions of Cyclic Imino Ethers. 4. Aromatic Poly(ester amide)s of the AA+BB Type on the Basis of 2-Oxazolines

Poly(ester amide)s were prepared by thermally initiated polymerization from two aromatic bis(2-oxazoline)s and four aromatic dicarboxylic acids. Polymerizations were performed in bulk and in solution. The structure of the polymers formed was confirmed by spectral analysis. The synthesis is limited by the thermal stability of the starting compounds. Limitation of the solution polymerization is the solubility of the starting compounds and the products in the solvent used. The prepared polymers have very good thermal properties.

Three isomeric forms of hydroxyphenyl-2-oxazoline: 2-(2-hydroxyphenyl)-2-oxazoline, 2-(3-hydroxyphenyl)-2-oxazoline and 2-(4-hydroxyphenyl)-2-oxazoline

Crystal structures are reported for three isomeric compounds, namely 2-(2-hydroxyphenyl)-2-oxazoline, (I), 2-(3-hydroxyphenyl)-2-oxazoline, (II), and 2-(4-hydroxyphenyl)-2-oxazoline, (III), all C9H9NO2 [systematic names: 2-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (I), 3-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (II), and 4-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (III)]. In these compounds, the deviation from coplanarity of the oxazoline and benzene rings is dependent on the position of the hydroxy group on the benzene ring. The coplanar arrangement in (I) is stabilized by a strong intramolecular O-H...N hydrogen bond. Surprisingly, the 2-oxazoline ring in molecule B of (II) adopts a 3T4 (C2TC3) conformation, while the 2-oxazoline ring in molecule A, as well as that in (I) and (III), is nearly planar, as expected. Tetramers of molecules of (II) are formed and they are bound together via weak C-H...N hydrogen bonds. In (III), strong intermolecular O-H...N hydrogen bonds and weak intramolecular C-H...O hydrogen bonds lead to the formation of an infinite chain of molecules perpendicular to the b direction. This paper also reports a theoretical investigation of hydrogen bonds, based on density functional theory (DFT) employing periodic boundary conditions.