Hyaluronan/Diethylaminoethyl Chitosan Polyelectrolyte Complexes as Carriers for Improved Colistin Delivery.

Improving the therapeutic characteristics of antibiotics is an effective strategy for controlling the growth of multidrug-resistant Gram-negative microorganisms. The purpose of this study was to develop a colistin (CT) delivery system based on hyaluronic acid (HA) and the water-soluble cationic chitosan derivative, diethylaminoethyl chitosan (DEAECS). The CT delivery system was a polyelectrolyte complex (PEC) obtained by interpolymeric interactions between the HA polyanion and the DEAECS polycation, with simultaneous inclusion of positively charged CT molecules into the resulting complex. The developed PEC had a hydrodynamic diameter of 210-250 nm and a negative surface charge (ζ-potential = -19 mV); the encapsulation and loading efficiencies were 100 and 16.7%, respectively. The developed CT delivery systems were characterized by modified release (30-40% and 85-90% of CT released in 15 and 60 min, respectively) compared to pure CT (100% CT released in 15 min). In vitro experiments showed that the encapsulation of CT in polysaccharide carriers did not reduce its antimicrobial activity, as the minimum inhibitory concentrations against Pseudomonas aeruginosa of both encapsulated CT and pure CT were 1 µg/mL.

Reactions of Cyclometalated Platinum(II) [Pt(N∧C)(PR3)Cl] Complexes with Imidazole and Imidazole-Containing Biomolecules: Fine-Tuning of Reactivity and Photophysical Properties via Ligand Design.

This work describes interaction of a family of [Pt(N∧C)(PR3)Cl] complexes with imidazole (Im), possible application of this chemistry for regioselective labeling of proteins through imidazole rings of histidine residues and employment of the resulting phosphorescent products in bioimaging. It was found that the complexes containing aliphatic phosphines display reversible substitution of chloride ligand for imidazole function that required considerable excess of imidazole to obtain full conversion into the substituted [Pt(ppy)(PR3)(Im)] product, whereas the substitution in the complexes with aromatic phosphines readily proceeds in 1:1.5 mixture of reagents. Rapid, selective, and quantitative coordination of imidazole to the platinum complexes enabled regioselective labeling of ubiquitin. X-ray protein crystallography of the {[Pt(ppy)(PPh3)]/ubiquitin} conjugate revealed direct bonding of the platinum center to unique histidine-68 residue through the nitrogen atom of imidazole function, the coordination being also supported by noncovalent interaction of the ligands with the protein secondary structure. The variations of the cyclometalating N∧C ligands gave a series of [Pt(N∧C)(PPh3)Cl] complexes (N∧C = 2-phenylpyridine, 2-(benzofuran-3-yl)pyridine, 2-(benzo[b]thiophen-3-yl)pyridine, methyl-2-phenylquinoline-4-carboxylate), which were used to investigate the impact of N∧C-ligand onto photophysical properties of the imidazole complexes and conjugates with human serum albumin (HSA). The chloride ligand substitution for imidazole and formation of the conjugates results in ignition of the platinum chromophore luminescence with substantially higher quantum yield in the latter case. Variation of the metalating N∧C-ligand made possible the shift of the emission to the red region of visible spectrum for both types of the products. Cell-viability tests revealed low cytotoxicity of all {[Pt(N∧C)(PPh3)Cl]/HSA} conjugates, while PLIM experiments demonstrated their high potential for oxygen sensing.

Hyaluronan/B12-chitosan polyelectrolyte complex for oral colistin administration.

Polyelectrolyte complexes (PECs) based on polysaccharides, including hyaluronic acid (HA) and chitosan (CS), are promising delivery systems for antimicrobial agents, including oral administration of the peptide antibiotic colistin (CT). Modification of CS with different targeting ligands to improve intestinal permeability is a suitable way to improve the oral bioavailability of polyelectrolyte particles. This study describes the procedure for obtaining CT-containing PECs based on HA and CS modified with cyanocobalamin (vitamin B12). In this case, vitamin B12 is used as a targeting ligand because it is absorbed in the ileum via specific transporter proteins. The resulting PECs had a hydrodynamic size of about 284 nm and a positive ζ-potential of about 26 mV; the encapsulation efficiency was 88.2 % and the CT content was 42.2 µg/mg. The developed systems provided a two-phase drug release: about 50 % of the CT was released in 0.5-1 h, and about 60 % of the antibiotic was cumulatively released in 5 h. The antimicrobial activity of encapsulated CT was maintained at the same level as the pure drug for at least 24 h (minimum inhibitory concentration against Pseudomonas aeruginosa was 2 µg/mL for both). In addition, the apparent permeability coefficient of CT in the PEC formulation was 2.4 × 10-6 cm/s. Thus, the incorporation of CT into HA- and vitamin B12-modified CS-based PECs can be considered as a simple and convenient method to improve the oral delivery of CT.

Hyaluronan/colistin polyelectrolyte complexes: Promising antiinfective drug delivery systems.

Nanotechnology-based modification of known antimicrobial agents is a rational and straightforward way to improve their safety and effectiveness. The aim of this study was to develop colistin (CT)-loaded polymeric carriers based on hyaluronic acid (HA) for potential application as antimicrobial agents against multi-resistant gram-negative microorganisms (including ESKAPE pathogens). CT-containing particles were obtained via a polyelectrolyte interaction between protonated CT amino groups and HA carboxyl groups (the CT-HA complex formation constant [logKCT-HA] was about 5.0). The resulting polyelectrolyte complexes had a size of 210-250 nm and a negative charge (ζ-potential -19 mV), with encapsulation and loading efficiencies of 100% and 20%, respectively. The developed CT delivery systems were characterized by modified release (45% and 85% of CT released in 15 and 60 min, respectively) compared to pure CT (100% CT released in 15 min). In vitro tests showed that the encapsulation of CT in polymer particles did not reduce its pharmacological activity; the minimum inhibitory concentrations of both encapsulated CT and pure CT were 1 µg/mL (against Pseudomonas aeruginosa).

Ni-functionalized submicron mesoporous silica particles as a sorbent for metal affinity chromatography.

In this research, a novel IMAC sorbent with high specificity for chlorine-containing compounds was developed. Ni-functionalized monodisperse spherical mesoporous silica particles of 500±25nm diameter were synthesized and their metal affinity properties were studied with the use of diclofenac as the model substance. The particles were aggregatively stable in the pH range of 3-12. The sorbent demonstrated a high adsorption capacity (0.60±0.06µg of DCF per 1mg of the sorbent) and high adsorption/desorption rate (20 and 5min was enough for the sorbent saturation and desorption of DCF, correspondingly). A mixture of eluents with addition of PFOS providing the almost complete recovery (98%) of diclofenac was first proposed. The monodispersity and the high sedimentation and aggregative stability of the particles provide the formation of a stable hydrosol even under ultrasound treatment which makes the mSiO2/Ni particles suitable for batch chromatography.

Self-assembly in aqueous solutions of imidazolium ionic liquids and their mixtures with an anionic surfactant.

Experimental data on micellization in aqueous solutions of 1-alkyl-3-methylimidazolium salts [C(n)mim]X and their mixtures with sodium dodecyl sulfate (NaDS) are reviewed. New results (the critical micelle concentration and enthalpy of micellization) are presented for mixtures of [C(4)mim]PF(6), [C(6)mim]BF(4), [C(6)mim]Br and [C(10)mim]Br with NaDS. Our data cover a wide range (from 0 to 0.9) of solvent-free based mole fractions of ionic liquid (IL). Even very small addition of ILs substantially decreases the cmc of NaDS due to the combined effect of electrostatic and hydrophobic interactions, and formation of mixed micelles. It is shown that the quasichemical aggregation model by Nagarajan and Ruckenstein may be successfully applied to aqueous solutions of long-chain ILs and their mixtures with NaDS. The local structure of micelles is obtained from all-atom MD simulations for [C(n)mim]Br and [C(n)mim]X+NaDS in aqueous medium.