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Syntheses and characterizations of biocompatible superparamagnetic iron oxide nanoparticles with embedded curcumin and coated with ultrathin layer of hyaluronic acid-curcumin (HA-Cur) conjugate have been reported. Zeta potential measurements confirmed effective coating of native iron oxide nanoparticles stabilized by cationic derivative of chitosan (SPION-CCh) with the synthesized HA-Cur conjugate. Both SPIONs with embedded curcumin and the ones coated with HA-Cur (SPION-CCh/HA-Cur) revealed desired magnetic characteristics while fluorescent properties were much better for the coated nanoparticles. SPION-CCh/HA-Cur nanoparticles were shown to be very promising candidates for T 2 MRI contrast agents as they can easily penetrate cell membrane and their relaxivity is exceptionally high (ca. 470mM -1 s -1 ). They may be also tracked using confocal fluorescence microscopy due to the presence of fluorescent curcumin in the coating. In vitro studies indicated that the obtained SPIONs-CCh/HA-Cur were non-toxic for EA.hy926 endothelial cells., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The parenteral anticoagulants may cause uncontrolled and life-threatening bleeding. Protamine, the only registered heparin antidote, is partially effective against low-molecular weight heparins, completely ineffective against fondaparinux and may cause unacceptable toxicity. Therefore, we aimed to develop a synthetic compound for safe and efficient neutralization of all parenteral anticoagulants. We synthesized pegylated PMAPTAC block copolymers, and then, we selected a lead heparin-binding copolymer (HBC). We assessed the effectiveness of HBC in the model of arterial thrombosis electrically induced in the carotid artery of rats by measuring thrombus weight, bleeding time, activated partial thromboplastin time, activated clotting time, and anti-factor Xa activity. The intravital tissue distribution, the cardiorespiratory, and organ toxicity were monitored. HBC diminished antithrombotic and anticoagulant effects of unfractionated heparin. Moreover, it stopped bleeding and completely reversed the enhancement of clotting times and anti-factor Xa activity caused by enoxaparin or fondaparinux. We observed slight pulmonary congestion and cell infiltration, but the cardiorespiratory parameters remained unchanged. We found a strong signal of fluorescently-labeled HBC in the urine, and a weaker in the liver and in the kidney. No signs of hepatic or nephrotoxicity were observed in the blood biochemistry or histopathologic examination. We developed a copolymer efficiently neutralizing effects of heparins in the living organism, which shows a very promising efficacy/safety profile and may help in the management of uncontrolled bleeding resulting from an anticoagulant injection. HBC could enable the safe replacement of unfractionated heparin with low-molecular weight heparins in patients undergoing cardiac surgery and complex vascular procedures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The mechanisms and factors causing or influencing degenerative diseases require tailor-made solutions. Natural polysaccharides are among the most versatile building units of the novel drug delivery systems. Their properties can be easily tailored to specific needs because they depend not only on the first-order structure, but also on the molecular weight, the type of end-groups and the conformation of the chain. The review presents the current state-of-art in the field of modifications of natural polysaccharides aiming at improving the delivery of anti-degenerative agents. Derivatization includes introducing of ionic or hydrophobic groups in order to adjust polarity or to obtain amphiphilic material, as well as degradable bonds, spacers and targeting moieties. The influence of the modification on the properties of the carrier, such as its size, surface charge, encapsulation efficiency, drug release profile, and stability in vivo, is discussed. Application of the polysaccharide derivatives to enhance the mucoadhesion and to actively target the drug to its site of action is also shown for a variety of carriers: nano and microparticulate systems, coated liposomes, hollow particles and polymer-drug conjugates.

Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions.We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer--Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5 ± 3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood, and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent. [ABSTRACT FROM AUTHOR]

Protamine, the only registered antidote of unfractionated heparin (UFH), may produce a number of adverse effects, such as anaphylactic shock or serious hypotension. We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce. As a starting material, we have chosen generally non-toxic, biocompatible, widely available, inexpensive, and easy to functionalize polysaccharides. Our approach was to synthesize, purify and characterize cationic derivatives of dextran, hydroxypropylcellulose, pullulan and γ-cyclodextrin, then to screen them for potential heparin-reversal activity using an in vitro assay and finally examine efficacy and safety of the most active polymers in Wistar rat and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation, activated partial thromboplastin time, bleeding time, and anti-factor Xa activity; safety studies included the measurement of hemodynamic, hematologic and immunologic parameters. Linear, high molecular weight dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3) is the most potent and the safest UFH inhibitor showing activity comparable to that of protamine while possessing lower immunogenicity. Cationic polysaccharides of various structures neutralize UFH. Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine. [ABSTRACT FROM AUTHOR]

new bilayer-coated microbeads for oral delivery of 5-aminosalicylic acid (5-ASA) were prepared from naturally occurring polysaccharides via emulsification method. 5-ASA was successfully encapsulated in chitosan-λ-carrageenan-coated alginate microbeads. The morphology and sizes of microparticles were studied using optical microscopy and dynamic light scattering. Drug release profiles were followed using high-performance liquid chromatography (HPLC) with spectrophotometric detection. The effect of chitosan thin layer and chitosan-λ-carrageenan bilayer on the drug release was studied at pH values simulating these characteristic for stomach (pH = 1.2) and intestine (pH = 7.4). Chitosan layer slightly increased 5-ASA release at pH = 1.2, whereas double-layer external coating decreased the release rates. Due to the bilayer properties, the micro-carriers were additionally protected against acidic conditions of the stomach and drug release in the intestine could be better controlled. [ABSTRACT FROM AUTHOR]

Highlights: [•] ι-Carrageenan was grafted with PNIPAM. [•] A novel thermoresponsive polyelectrolyte was obtained. [•] Polymer shows LCST close to that characteristic of PNIPAM homopolymer. [•] Polymer interacts with DTAC, a model cationic surfactant. [•] The nature of these interactions is different than that for the native carrageenan. [ABSTRACT FROM AUTHOR]

Cationic derivatives of dextran (Dex) and hydroxypropylcellulose (HPC) were studied as potential alternatives of protamine sulfate (PS) used in the reversal of anticoagulant activity of heparin. The modification was performed by the attachment of cationic groups to the Dex main chain or by grafting short side chains of a polycation onto HPC. The cationic derivatives of these polysaccharides were found to bind heparin with the efficiency increasing with growing degree of cationic modification. The degree of cationic modification and consequently the ζ potential of the polymers do not have to be high to achieve effective heparin binding. The size of the complexes of cationic Dex with unfractionated heparin (UFH) is a few micrometers. For complexes of cationic HPC and UFH the size is much below 1 μm, both below and above the lower critical solution temperature of HPC. None of the cationic polysaccharides studied caused hemolysis. The concentrations of the polymers inducing the aggregation of human erythrocytes in vitro were determined. [ABSTRACT FROM AUTHOR]