Christo B. Tsvetanov

Stabilized micelles as delivery vehicles for paclitaxel

Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol(®)), longer mean residence time (9-times longer than i.v. Taxol(®)) and high distribution volume (2-fold higher than i.v. Taxol(®)) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol(®), in particular higher area under curve (1.2-fold), 5-times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles.

Stabilization of polymeric micelles with a mixed poly(ethylene oxide)/poly(2-hydroxyethyl methacrylate) shell by formation of poly(pentaerythritol tetraacrylate) nanonetworks within the micelles

Polymeric micelles comprising a mixed poly(ethylene oxide) (PEO)/poly(2-hydroxyethyl methacrylate) (PHEMA) shell and a thermosensitive poly(propylene oxide) (PPO) core were prepared in aqueous media and stabilized by UV-induced free radical polymerization of pentaerythritol tetraacrylate (PETA). The micelles were formed from PEO75PPO30PEO75 and PHEMA15PPO33PHEMA15 triblock copolymers mixed at different weight ratios. The micellar morphology in aqueous solution at different concentrations, ultrasonic irradiation, and in methanol was investigated by dynamic light scattering and scanning force microscopy. The results indicate that the stabilized polymeric micelles with a mixed shell maintain their morphology under different conditions emphasizing the efficiency of the stabilizing method employed.

Innovative approach for stabilizing poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) micelles by forming nano-sized networks in the micelle

Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (F-68) micelles were stabilized by UV-induced free-radical polymerisation of pentaerythritol tetraacrylate (PETA). The polymerisation resulted in the formation of an interpenetrating network of poly(PETA) and polyether chains, which was restricted only to specific nanodomains (nano-networks) within the micelles as shown by the TEM analysis. Depending on the experimental conditions stabilized polymeric micelles (SPMs) with spherical shape and sizes in the 32–50 nm range were obtained. SPMs stability in aqueous media at concentrations significantly lower than the critical micelle concentration (CMC) of free F-68 was demonstrated using dynamic light scattering and the diphenylhexatriene (DPH) solubilization technique. Furthermore, the stabilized F-68 micelles maintained their size and structure even when subjected to 20 kHz ultrasonic irradiation.

Polymeric nanoparticle engineering: from temperature-responsive polymer mesoglobules to gene delivery systems.

A novel approach for the preparation of nano- and microcapsules in aqueous solutions by using thermoresponsive polymer (TRP) templates (mesoglobules) is described. The method comprised three steps: formation of mesoglobules, coating the templates by seeded radical copolymerization, followed by core dissolution and core removal upon cooling. When mesoglobule entraps biomacromolecules during the process of their formation, it makes it possible to load a controlled amount of bioactive compounds without covalent attachment. Special attention is paid to the mesoglobule dissolution upon cooling, as well as their loading efficiency. Details on the outer shell formation and the possibilities for targeting ligands incorporation and control of the shell porosity are discussed. Finally, the seeded radical copolymerization was used for covering DNA complexes with cationic copolymers bearing TRP blocks. This Review is an attempt to convince researchers of the promising perspectives for using mesoglobules as potential reservoirs, carriers, and transferring agents for biologically active substances.

Epoxidation of styrene with hydrogen peroxide in the presence of polymer-supported quaternary ammonium salts and peroxo complexes of W(VI)

Abstract Quaternary ammonium salts immobilized onto poly(2- N , N -dimethylaminoethyl) methacrylate and a mixed network of poly(oxyethylene) and poly(4-vinylpyridine) were prepared. These salts were characterized by an elemental analysis, IR, 1 H and 13 C NMR spectroscopy. The catalytic activity of the polymeric complexes was studied in the epoxidation of styrene as a model reaction. The system under study consisted of a water-immiscible solvent, aqueous hydrogen peroxide and Na 2 WO 4 /H 3 PO 4 . The catalytic activity of the polymeric ammonium salts depends on the kind of support employed, as well as on the length of hydrocarbon radicals and the nature of the anion. An increase in the selectivity of the reaction as compared to a system with non-immobilized salts is observed.

Wormlike Morphology Formation and Stabilization of “Pluronic P123” Micelles by Solubilization of Pentaerythritol Tetraacrylate

A transition from spherical to wormlike micelles of a poly(ethylene oxide) 20- block-poly(propylene oxide) 70- block-poly(ethylene oxide) 20 triblock copolymer Pluronic P123 induced by solubilization of a tetrafuctional monomer, Pentaerythritol tetraacrylate (PETA), in aqueous media has been studied. The wormlike micelles shape was locked by UV cross-linking of PETA within the micelles resulting in stabilized polymeric micelles (SPMs). The stability of SPMs in a good solvent for both polyether blocks like THF, and upon dilution below the critical micelle concentration (CMC) of P123 in water was confirmed by dynamic light scattering (DLS) and scanning force microscopy (SFM). Formation of cadmium sulfide (CdS) nanoparticles within the wormlike SPMs was carried out via the reduction of Cd (2+) with NaS and analyzed by transmission electron microscopy (TEM) and UV-vis absorption measurements. A stable water-dispersible hybrid system consisting of CdS quantum dots embedded into the wormlike SPMs was obtained.

UV‐Initiated Crosslinking of Poly(ethylene oxide) with Pentaerythritol Triacrylate in Solid State

A procedure for effective crosslinking of solid films of poly(ethylene oxide) (PEO) by UV irradiation in the presence of pentaerythritol triacrylate (PETA) as a crosslinking agent was developped. UV crosslinking of commercial PEO powder as a hydrocarbon dispersion containing PETA was found to be very effective as well. The polymer gels obtained were free from low molecular aromatic impurities which are inevitable if photoinitiators are used. UV irradiation in the presence of PETA seems to be a simple method for obtaining films or powderlike products of PEO based hydrogels.

Rheology of Aqueous Solutions of Polyglycidol-Based Analogues to Pluronic Block Copolymers

The aqueous solution properties of a series of polyglycidol-poly(propylene oxide)-polyglycidol (PG-PPO-PG) block copolymers were investigated by means of rheology. The copolymers are considered as analogues to the commercially available Pluronic, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), block copolymers in which the flanking PEO blocks are substituted by blocks of structurally similar PG bearing a hydroxyl group in each repeating monomer unit. In the dilute regime, the samples normally behave as Newtonian fluids. Shear thinning was observed only for the solutions of LGP65 (the copolymer of 50 wt % PG content) as well as at concentrations well above the critical micellization concentration for the rest of the copolymers. The zero shear viscosities exhibited pronounced maxima at PG content of 50 wt % and were found to decrease with increasing temperature. The concentrated solutions were investigated using oscillatory measurements. Large hystereses were observed during the temperature sweeps 15-70-15 degrees C. The evolutions of the loss and storage moduli with frequency, PG content, and temperature displayed transitions from a non-elastic to elastic behavior of the solutions. A phase diagram showing areas of predominant elasticity or fluidity was constructed.

On the nature of the active centres in the initial stages of methacrylonitrile anionic polymerization—I: Spectral studies

Abstract The active centres in the initial stage of methacrylonitrile anionic polymerization have been studied by means of electronic and i.r.-spectra as well as by use of model compounds. The attachment of the first monomer unit to the initiator causes formation of the carbanion , characterized by an absorption band at 2020–2055 cm −1 . Addition of more monomer units leads to the appearance of a new band at 2100 cm −1 , due to the group . The appearance of a new band at 2260 cm −1 and the shift of the band at 2020–2055 cm −1 towards higher frequencies, as the number of adjacent monomer units is increased, is explained by interaction of the active centres with the nitrile groups of the polymer chain.

A mild and versatile approach for DNA encapsulation

The complex between polycation-containing thermally sensitive block copolymer and DNA (polyplex) was stabilized utilizing a seeded radical copolymerization in aqueous media under mild conditions. Thus, the DNA molecule was encapsulated into the core of a stable nanoparticle with a cross-linked polymer shell and size of ∼100 nm. The versatility of the proposed approach was demonstrated through the introduction of targeting and biodegradable functions during the polymer shell formation providing an opportunity to construct gene carriers that are able to satisfy the conflicting requirements of adequate DNA protection and efficient release into the target cell.