Self-Assembling Injectable Hydrogel for Controlled Drug Delivery of Antimuscular Atrophy Drug Tilorone.

A two-component injectable hydrogel was suitably prepared for the encapsulation and prolonged release of tilorone which is an antimuscular atrophy drug. The rapid (7-45 s, depending on the polymer concentration) in situ solidifications of the hydrogel were evoked by the evolving Schiff-base bonds between the aldehyde groups of modified PVA (4-formyl benzoate PVA, PVA-CHO, 5.9 mol% functionalization degree) and the amino groups of 3-mercaptopropionate chitosan (CHIT-SH). The successful modification of the initial polymers was confirmed by both FTIR and NMR measurements; moreover, a new peak appeared in the FTIR spectrum of the 10% w/v PVA-CHO/CHIT-SH hydrogel at 1647 cm-1, indicating the formation of a Schiff base (-CH=N-) and confirming the interaction between the NH2 groups of CHIT-SH and the CHO groups of PVA-CHO for the formation of the dynamic hydrogel. The reaction between the NH2 and CHO groups of the modified biopolymers resulted in a significant increase in the hydrogel's viscosity which was more than one thousand times greater (9800 mPa·s) than that of the used polymer solutions, which have a viscosity of only 4.6 and 5.8 mPa·s, respectively. Furthermore, the initial chitosan was modified with mercaptopropionic acid (thiol content = 201.85 ± 12 µmol/g) to increase the mucoadhesive properties of the hydrogel. The thiolated chitosan showed a significant increase (~600 mN/mm) in adhesion to the pig intestinal membrane compared to the initial one (~300 mN/mm). The in vitro release of tilorone from the hydrogel was controlled with the crosslinking density/concentration of the hydrogel; the 10% w/v PVA-CHO/CHIT-SH hydrogel had the slowest releasing (21.7 h-1/2) rate, while the 2% w/v PVA-CHO/CHIT-SH hydrogel had the fastest releasing rate (34.6 h-1/2). Due to the characteristics of these hydrogels, their future uses include tissue regeneration scaffolds, wound dressings for skin injuries, and injectable or in situ forming drug delivery systems. Eventually, we hope that the developed hydrogel will be useful in the local treatment of muscle atrophy, such as laryngotracheal atrophy.

Preparation and detailed characterization of the thiomer chitosan-cysteine as a suitable mucoadhesive excipient for nasal powders.

The therapeutic application of nasal powders requires the development of novel mucoadhesive excipients. Thiolated polymers exhibit significant potential for this purpose based on their increased mucoadhesion attributable to the formation of disulfide bonds between the polymer and mucus surface. A chitosan-cysteine (chit-cyst) conjugate was synthesized using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide in aqueous solution. The synthetic yield and synthesis conditions were optimized, and the efficiency of the reaction was evaluated. Rheological measurements revealed that the polymer derivative exhibited increased mucoadhesive properties in comparison to chitosan powder. To characterize the polymer, a novel purity investigation method was developed and verified to investigate the residual l-cysteine content. The results revealed that l-cysteine was not detectable in the resultant polymer matrix. Based on the cytotoxicity studies, chit-cyst was found to be safe for nasal application. Thereafter, nasal powder formulations were prepared using the polymer and the antiparkinsonian drug levodopa methyl ester hydrochloride by freeze-drying to investigate their nasal applicability. Based on the in vitro studies, these powders might be suitable for reducing the off periods of Parkinson's disease because of their expected higher in vivo mucoadhesion.

Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer, Antifibrotic and Antibacterial Mitomycin.

Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h-n); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h-n) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.

Biocompatible poly(ethylene succinate) polyester with molecular weight dependent drug release properties.

In the present study, we demonstrate that well-known molecular weight-dependent solubility properties of a polymer can also be used in the field of controlled drug delivery. To prove this, poly(ethylene succinate) (PES) polyesters with polycondensation time regulated molecular weights were synthesized via catalyst-free direct polymerization in an equimolar ratio of ethylene glycol and succinic acid monomers at 185 °C. DSC and contact angle measurements revealed that increasing the molecular weight (Mw, 4.3-5.05 kDa) through the polymerization time (40-80 min) increased the thermal stability (Tm= ∼61-80 °C) and slightly the hydrophobicity (Θw= ∼27-41°) of the obtained aliphatic polyester. Next, this biodegradable polymer was used for the encapsulation of Ca2+ channel blocker Nimodipine (NIMO) to overcome the poor water solubility and enhance the bioavailability of the drug. The drug/ polymer compatibility was proved by the means of solubility (δ) and Flory-Huggins interaction (miscibility) parameters (χ). The nanoprecipitation encapsulation of NIMO into PES with increasing Mw resulted in the formation of spherical 270 ± 103 nm NIMO-loaded PES nanoparticles (NPs). Furthermore, based on the XRD measurements, the encapsulated form of NIMO-loaded PES NPs showed lower drug crystallinity, which enhanced not only the water solubility but even the water stability of the NIMO in an aqueous medium. The in-vitro drug release experiments demonstrated that the release of NIMO drug could be accelerated or even prolonged by the molecular weights of PES as well. Due to the low crystallinity of PES polyester and low particle size of the encapsulated NIMO drug led to enhance solubility and releasing process of NIMO from PES with lower Mw (4.3 kDa and 4.5 kDa) compared to pure crystalline NIMO. However, further increasing the molecular weight (5.05 kDa) was already reduced the amount of drug release that provides the prolonged therapeutic effect and enhances the bioavailability of the NIMO drug.

The Effect of Molecular Weight on the Solubility Properties of Biocompatible Poly(ethylene succinate) Polyester.

Poly(ethylene succinate) (PES) is one of the most promising biodegradable and biocompatible polyesters and is widely used in different biomedical applications. However, little information is available on its solubility and precipitation properties, despite that these solution behavior properties affect its applicability. In order to systematically study these effects, biodegradable and biocompatible poly(ethylene succinate) (PES) was synthesized using ethylene glycol and succinic acid monomers with an equimolar ratio. Despite the optimized reaction temperature (T = 185 °C) of the direct condensation polymerization, relatively low molecular mass values were achieved without using a catalyst, and the Mn was adjustable with the reaction time (40-100 min) in the range of ~850 and ~1300 Da. The obtained crude products were purified by precipitation from THF ("good" solvent) with excess of methanol ("bad" solvent). The solvents for PES oligomers purification were chosen according to the calculated values of solubility parameters by different approaches (Fedors, Hoy and Hoftyzer-van Krevelen). The theta-solvent composition of the PES solution was 0.3 v/v% water and 0.7 v/v% DMSO in this binary mixture. These measurements were also allowed to determine important parameters such as the coefficients A (=0.67) and B (=3.69 × 104) from the Schulz equation, or the Kη (=8.22 × 10-2) and α (=0.52) constants from the Kuhn-Mark-Houwink equation. Hopefully, the prepared PES with different molecular weights is a promising candidate for biomedical applications and the reported data and constants are useful for other researchers who work with this promising polyester.

Photocatalytic elimination of interfacial water pollutants by floatable photoreactive composite nanoparticles.

Disastrous oil spills cause severe environmental issues. The shortcomings of current cleaning methods for remediating oil have prompted the latest research drive to create intelligent nanoparticles that absorb oil. We, therefore, synthesized 197 ± 50 nm floatable photoreactive hybrid nanoparticles with Ag-TiO2 plasmonic photocatalyst (Eg = 3.08 eV) content to eliminate interfacial water pollutants, especially toluene-based artificial oil spill. We found that the composite particles have non-wetting properties in the aqueous media and float easily on the surface of the water due to the moderate hydrophobic nature (Θ = 113°) of the matrix of polystyrene, and these properties lead to elevated absorption of the interfacial organic pollutants (e.g., mineral oil). We showed that (28.5 mol%) divinylbenzene cross-linker content was required for adequate swelling capacity (2.15 g/g), whereas incorporated 15.8% Ag-TiO2 content in the swollen particles was enough for efficient photodegradation of the artificial oil spill under 150 min LED light (λmax = 405 nm) irradiation. The swollen polymer particles with embedded 32 ± 7 nm Ag-TiO2 content increase the efficiency of photooxidation by increased the direct contact between both the photocatalysts and the artificial oil spill. Finally, it was also presented that the composite particles destroy themselves: after approximately one and a half months of continuous LED light irradiation, the organic polymer component of the composite was almost completely (88.5%) photodegraded by the incorporated inorganic photocatalyst particles.

Preparation of novel tissue acidosis-responsive chitosan drug nanoparticles: Characterization and in vitro release properties of Ca2+ channel blocker nimodipine drug molecules.

The pH-responsive intelligent drug release facility of hydrophobically modified chitosan nanoparticles (Chit NPs) (d = 5.2 ±â€¯1.1 nm) was presented in the case of poorly water soluble Ca2+ channel blocker nimodipine (NIMO) drug molecules. The adequate pH-sensitivity, i.e. the suitable drug carrier properties of the initial hydrophilic Chit were achieved by reductive amination of Chit with hexanal (C6-) and dodecanal (C12-) aldehydes. The successful modifications of the macromolecule were evidenced via FTIR measurements: the band appearing at 1412 cm-1 (CN stretching in aliphatic amines) in the cases of the hydrophobically modified Chit samples shows that the CN bond successfully formed between the Chit and the aldehydes. Hydrophobization of the polymer unambiguously led to lower water contents with lower intermolecular interactions in the prepared hydrogel matrix: the initial hydrophilic Chit has the highest water content (78.6 wt%) and the increasing hydrophobicity of the polymer resulted in decreasing water content (C6-chit.: 74.2 wt% and C12-chit.: 47.1 wt%). Furthermore, it was established that the length of the side chain of the aldehyde influences the pH-dependent solubility properties of the Chit. Transparent homogenous polymer solution was obtained at lower pH, while at higher pH the formation of polymer (nano)particles was determined and the corresponding cut-off pH values showed decreasing tendency with increasing hydrophobic feature (pH = 7.47, 6.73 and 2.49 for initial Chit, C6-chit and C12-chit, respectively). Next the poorly water soluble NIMO drug was encapsulated with the C6-chit with adequate pH-sensitive properties. The polymer-stabilized NIMO particles with 10 wt% NIMO content resulted in stable dispersion in aqueous phase, the formation of polymer shell increased in the water solubility/dispersibility of the initial hydrophobic drug. According to the drug release experiments, we clearly confirmed that the encapsulated low crystallinity NIMO drug remained closed in the polymer NPs at normal tissue pH (pH = 7.4, PBS buffer, physiological condition) but at pH < 6.5 which is typical for seriously ischemic brain tissue, 93.6% of the available 0.14 mg/ml NIMO was released into the buffer solution under 8 h release time. According to this in vitro study, the presented pH-sensitive drug carrier system could be useful to selectively target ischemic brain regions characterized by acidosis, to achieve neuroprotection at tissue zones at risk of injury, without any undesirable side effects caused by systemic drug administration.

Autochthonous ascomycetes in depollution of polychlorinated biphenyls contaminated soil and sediment.

We investigated the capacity of a consortium of ascomycetous strains, Doratomyces nanus, Doratomyces purpureofuscus, Doratomyces verrucisporus, Myceliophthora thermophila, Phoma eupyrena and Thermoascus crustaceus in the mycoremediation of historically contaminated soil and sediment by polychlorinated biphenyls (PCBs). Analyses of 15 PCB concentrations in three mesocosms containing soil from which the fungal strains had previously been isolated, revealed significant PCB depletions of 16.9% for the 6 indicator PCBs (i-PCBs) and 18.7% for the total 15 PCBs analyzed after 6months treatment. The degradation rate did not statistically vary whether the soil had been treated with non-inoculated straw or colonized straw or without straw and inoculated with the consortium of the six strains. Concerning the sediment, we evidenced significant depletions of 31.8% for the 6 i-PCBs and 33.3% for the 15 PCB congeners. The PCB depletions affected most of the 15 PCBs analyzed without preference for lower chlorinated congeners. Bioaugmented strains were evidenced in different mesocosms, but their reintroduction, after six months treatment, did not improve the rate of PCB degradation, suggesting that the biodegradation could affect the bioavailable PCB fraction. Our results demonstrate that the ascomycetous strains potentially adapted to PCBs may be propitious to the remediation of PCB contaminated sites.

Leaching behaviour of hazardous demolition waste.

Demolition wastes are generally disposed of in unlined landfills for inert waste. However, demolition wastes are not just inert wastes. Indeed, a small fraction of demolition waste contains components that are hazardous to human health and the environment, e.g., lead-based paint, mercury-contained in fluorescent lamps, treated wood, and asbestos. The objective of this study is to evaluate the release potential of pollutants contained in these hazardous components when they are mixed with inert wastes in unlined landfills. After identification of the different building products which can contain hazardous elements and which can be potentially pollutant in landfill scenario, we performed leaching tests using three different lysimeters: one lysimeter containing only inert wastes and two lysimeters containing inert wastes mixed with hazardous demolition wastes. The leachates from these lysimeters were analysed (heavy metals, chlorides, sulphates fluoride, DOC (Dissolved Organic Carbon), phenol index, and PAH). Finally, we compared concentrations and cumulative releases of elements in leachates with the limits values of European regulation for the acceptance of inert wastes at landfill. Results indicate that limit values are exceeded for some elements. We also performed a percolation column test with only demolition hazardous wastes to evaluate the specific contribution of these wastes in the observed releases.