Optimized protocol for the radioiodination of hydrazone-type polymer drug delivery systems
Applied Radiation and Isotopes, 2015
Hydrazone conjugates of polymers with doxorubicin represent a very promising tool for cancer chem... more Hydrazone conjugates of polymers with doxorubicin represent a very promising tool for cancer chemotherapy. However, these conjugates are very difficult to radiolabel with iodine radionuclides, which possess otherwise very advantageous nuclear properties to, e.g., follow biodistribution. In this study, we developed a robust protocol for the high-yield radioiodination of hydrazone-type drug delivery systems with doxorubicin. In particular, it is crucial that the polymer radioiodination step be performed before the deprotection of the hydrazide and doxorubicin binding.
Smart polymers in drug delivery systems on crossroads: Which way deserves following?
European Polymer Journal, 2015
ABSTRACT A feature article is presented on recent developments in the investigation of stimuli re... more ABSTRACT A feature article is presented on recent developments in the investigation of stimuli responsive polymers and their biomedical applications. Polymer systems are grouped with respect to sensitivity to changes in temperature, pH, light, redox potential and other special changes in environment. Underlying principles and possible applications of various systems are discussed. Critical evaluation of all benefits but also drawbacks of a particular stimuli responsivity is therefore necessary when planning the construction of multi-stimuli responsive systems. Special focus is devoted to biological consequences of physico-chemical properties of the polymer materials.
Selective Uptake and Separation of Oxoanions of Molybdenum, Vanadium, Tungsten, and Germanium by Synthetic Sorbents Having Polyol Moieties and Polysaccharide-Based Biosorbents
Fundamentals and Applications of Anion Separations, 2004
Preparation of stable Pd nanocubes and their use in biological labeling
Colloids and Surfaces B: Biointerfaces, 2012
Stable Pd nanocubes (PdNC) with the average size ~15 nm were prepared by the controlled reduction... more Stable Pd nanocubes (PdNC) with the average size ~15 nm were prepared by the controlled reduction of sodium tetrachloropalladate with ascorbic acid in water, in the presence of polyvinylpyrrolidone and potassium bromide. Morphology of the particles was characterized by transmission electron microscopy (TEM) and their stability in the colloidal solution was verified by dynamic light scattering (DLS). It has been demonstrated that the Pd nanocubes can be distinguished from commercial Au nanospheres in a standard TEM microscope by means of automated image analysis. In the next step, the PdNC were successfully conjugated to immunoglobulin proteins and used for the detection of a specific protein (nucleophosmin) on ultrathin sections of HeLa cells. Our experiments showed that PdNC can be used for multiple immunolabeling in combination with commercial Au nanospheres.
Chelating polymeric particles intended for the therapy of Wilson’s disease
Reactive and Functional Polymers, 2013
ABSTRACT Wilson’s disease is a genetic disorder that leads to a high accumulation of copper in mu... more ABSTRACT Wilson’s disease is a genetic disorder that leads to a high accumulation of copper in multiple organs with subsequent toxic effects. In this paper, a gentle therapy to eliminate harmful copper concentrations in patients with Wilson’s disease is proposed using an oral administration of insoluble polymeric sorbents containing selective chelating groups for copper(II). The sorbents contained triethylenetetramine, N,N-di(2-pyridylmethyl)amine, 8-hydroxyquinoline or 8-hydroxyquinoline-5-sulfonic acid chelating groups bound to a methacrylate-based macroporous support. Nearly quantitative copper(II) uptake within minutes was achieved in buffers modeling the pH range present in the gastric environment (pH 2.0 and 4.0). The sorbents demonstrated chelating selectivity for copper(II) against zinc(II) with ratios of up to 1321. The sorbents demonstrated sufficient stability of the copper complexes against rechelation using studies in a model environment for the small intestine (the presence of chelating amino acids, pH 6.8).
The temperature-driven self-assembly of nonionic amphiphilic tailor-made triblock copolymers has ... more The temperature-driven self-assembly of nonionic amphiphilic tailor-made triblock copolymers has been studied by DLS, NMR, ITC, and SAXS. The composition of these triblock copolymers is more complex than that of the vast majority of poly(2-alkyl-2oxazoline)s: a statistical thermoresponsive (iPrOx) and hydrophobic (BuOx) central block with terminal hydrophilic blocks (MeOx). In general, as temperature increases, nanoparticles form in a process starting with single molecules that become loose aggregates and ends with the formation of compact nanoparticles. Here, we first attempt to resolve the effects of each block on nanoparticle formation. It has been proven that the iPrOx/MeOx ratio determines the value of the cloud point temperature, whereas the different BuOx−iPrOx blocks determine the character of the process. Finally, we complete our investigation by presenting the thermodynamic and structural profiles of the complexation between these triblock poly(2-alkyl-2-oxazoline)s and two ionic surfactants. The addition of an ionic surfactant promotes a rearrangement of the polymer molecules and the formation of complexes followed by the appearance of polymer−surfactant hybrid micelles. Analysis of the interaction shows a strong and nonspecific reaction between the polymers and the anionic surfactant sodium dodecyl sulfate and weak but polymer-state-sensitive interactions between the polymer and the cationic surfactant hexadecyltrimethylammonium bromide.
This study is focused on thermoresponsive glycogen-graft-poly(2-alkyl-2-oxazolines), a new group ... more This study is focused on thermoresponsive glycogen-graft-poly(2-alkyl-2-oxazolines), a new group of nanostructured hybrid dendrimeric stimuli-responsive polymers connecting the body's own biodegradable polysaccharidic dendrimer glycogen with the widely tuneable thermoresponsive behavior of polypeptide-analogic poly(2-alkyl-2-oxazolines), which are known to be biocompatible. Glycogengraft-poly(2-alkyl-2-oxazolines) were prepared by a simple one-pot two-step procedure involving cationic ring-opening polymerization of 2-alkyl-2-oxazolines followed by termination of the living cationic ends with sodium glycogenate. As confirmed by light and X-ray scattering, as well as cryotransmission electron microscopy, the grafted dendrimer structure allows easy adjustment of the cloud point temperature, the concentration dependence and nanostructure of the self-assembled phase separated polymer by crosstalk during graft composition, the graft length and the grafting density, in a very wide range.
Fine tuning of the pH-dependent drug release rate from polyHPMA-ellipticinium conjugates
Bioorganic & Medicinal Chemistry, 2013
Polymer conjugates of anticancer drugs have shown high potential for assisting in cancer treatmen... more Polymer conjugates of anticancer drugs have shown high potential for assisting in cancer treatments. The pH-labile spacers allow site-specific triggered release of the drugs. We synthesized and characterized model drug conjugates with hydrazide bond-containing poly[N-(2-hydroxypropyl)methacrylamide] differing in the chemical surrounding of the hydrazone bond-containing spacer to find structure-drug release rate relationships. The conjugate selected for further studies shows negligible drug release in a pH 7.4 buffer but released 50% of the ellipticinium drug within 24h in a pH 5.0 phosphate saline buffer. The ellipticinium drug retained the antiproliferative activity of the ellipticine.
Silver-coated monolithic columns for separation in radiopharmaceutical applications
Journal of Separation Science, 2014
In this study, we demonstrate the preparation of a macroporous monolithic column containing ancho... more In this study, we demonstrate the preparation of a macroporous monolithic column containing anchored silver nanoparticles and its use for the elimination of excess radioiodine from the radiolabeled pharmaceutical. The poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith was first functionalized with cystamine and the free thiol groups liberated by reaction with borohydride. In-house-prepared silver nanoparticles were then attached by interaction with the surface thiols. The deiodization process was demonstrated with the commonly used radiopharmaceutical m-iodobenzylguanidine labeled with radionuclide iodine-125.
Poly(2-Oxazoline)s - Are They More Advantageous for Biomedical Applications Than Other Polymers?
Macromolecular Rapid Communications, 2012
Poly(2-alkyl-2-oxazoline)s are biocompatible polymers with polypeptide-isomeric structures that a... more Poly(2-alkyl-2-oxazoline)s are biocompatible polymers with polypeptide-isomeric structures that are attracting increasing interest as biomaterials for drug, gene, protein, and radionuclide delivery. They are, however, still relatively new in comparison to other classes of hydrophilic water-soluble polymers already established for such use, including poly(ethylene oxide), polyvinylpyrrolidone, and polymethacrylamides such as poly[N-(2-hydroxypropyl)methacrylamide]. This feature article critically compares the synthetic aspects and physicochemical and biological properties of poly(2-alkyl-2-oxazoline)s and these commonly studied polymers in terms of their suitability for biomedical applications.
Abstracts 235 SM on FTSM. We observed acantholysis in the stratum spinosum as well as epidermal-d... more Abstracts 235 SM on FTSM. We observed acantholysis in the stratum spinosum as well as epidermal-dermal separation in SM treated FTSMs 24 h after exposure. Antibodies to collagen IV and pan-cytokeratin showed no changed immunoreactivity 24 h after exposure to SM. This is in agreement with earlier in vivo-studies by Smith et al. (1998). These features suggest that a part of the mechanism of action of SM is a direct effect on the basal membrane zone.
Propolis is a resinous product collected by honeybees from various plant sources; it is widely us... more Propolis is a resinous product collected by honeybees from various plant sources; it is widely used in traditional medicine and has been reported to have a broad spectrum of pharmacological effects (i.e., antibacterial, antifungal, antiviral and anti-inflammatory effects). The most commonly used propolis formulations are gargles, in which propolis tinctures are diluted with water. The dilution process is accompanied by nanoprecipitation, and the propolis droplets are dispersed in the prepared gargle. In the present study, we investigated the dependence of the properties of propolis nanodispersions on the method of preparation. The particle size was found to be approximately 150 nm and was observed to decrease with increasing dilution as the zeta potential of the particles became more negative, which stabilized the dispersion. The dispersion dissolved upon alkalization and reprecipitated during acidification. The addition of salt destabilized the dispersion. The uptake of propolis from the dispersion was modeled using 1-octanol and was found to be rapid and only slightly dependent on the nanoparticle size. Propolis susceptibility tests showed that the most effective dispersion of propolis was tenfold-diluted EEP (P-80-10 and JP-80-10). The disc diffusion method was used to evaluate the antibacterial activity of chosen dispersions of propolis against Staphylococcus aureus, Escherichia coli and Candida albicans. Propolis samples with different locations of origin exhibited different effects against the strain of C. albicans.
The simultaneous combination of optical and magnetic resonance imaging (MRI) would greatly benefi... more The simultaneous combination of optical and magnetic resonance imaging (MRI) would greatly benefit in vivo disease diagnosis as well as in situ monitoring of living cells. In order to design dual detection of cells involving simultaneous imaging by fluorescent microscopy and MRI, nanoparticles with two reporters, a fluorescent dye and a superparamagnetic core, included in one particle were synthesized and characterized. The g-Fe 2 O 3 nanoparticles obtained by coprecipitation and oxidation were coated with silica (SiO 2 ) or carboxymethyl chitosan (CMCS) and labeled with fluorescein isothiocyanate (FITC). The fluorescent label was covalently bound to the nanoparticles and was not quenched by the iron oxide core. The nanoparticles successfully labeled rat mesenchymal stem cells (rMSCs) in vitro. Relaxation time measurements found large amounts of iron inside the cells with FITC-labeled g-Fe 2 O 3 -SiO 2 -AP nanoparticles. Both MR and fluorescent imaging of a rat brain with implanted rMSCs labeled with FITC-labeled CMCS-modified silica-coated g-Fe 2 O 3 nanoparticles were performed.
handle, clinically applicable formulation for ultrasound controlled release of the model chemothe... more handle, clinically applicable formulation for ultrasound controlled release of the model chemotherapeutic drug: Doxorubicin (DOX).
We describe the synthesis of new crosslinker N 0 -{3- [2-(4-{2-[3-(methacryloylamino)propanoyl]hy... more We describe the synthesis of new crosslinker N 0 -{3- [2-(4-{2-[3-(methacryloylamino)propanoyl]hydra-zono}cyclohexyliden)hydrazino]-3-oxopropyl}-2-methylacrylamide, which is stable at physiological pH, but is hydrolytically cleaved in acidic pH. Study of acid hydrolysis showed that the crosslinker is hydrolyzed into two N 0 -(3-hydrazino-3-oxopropyl)-2-methylacrylamide molecules and one 1,4-cyclohexanedione molecule. Hydrogels based on poly[N-(2-hydroxypropyl)methacrylamide] crosslinked with this crosslinker were prepared and their degradation rate was studied as a function of pH (in the range of pH 1.5e7.4). The hydrogel is cleaved within 8e27 days at pH between 1.5 and 6 and is stable at pH 7.4 making it promising for the construction of oesophageal stents.
Polymer conjugates of acridine-type anticancer drugs with pH-controlled activation
Bioorganic & Medicinal Chemistry, 2012
Acridines are potent DNA-intercalating anticancer agents with high in vivo anticancer effectivene... more Acridines are potent DNA-intercalating anticancer agents with high in vivo anticancer effectiveness, but also severe side effects. We synthesized five 9-anilinoacridine-type drugs and their conjugates with biocompatible water-soluble hydrazide polymer carrier. All of the synthesized acridine drugs retained their in vitro antiproliferative properties. Their polymer conjugates were sufficiently stable at pH 7.4 (model of pH in blood plasma) while releasing free drugs at pH 5.0 (model of pH in endosomes). After internalization of the conjugates, the free drugs were released and are visible in cell nuclei by fluorescence microscopy. Their intercalation ability was proven using a competitive ethidium bromide displacement assay.
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