Lower critical solution temperature versus volume phase transition temperature in thermoresponsive drug delivery systems

One of the most subtle problem in the characterization of thermoresponsive polymers is the evaluation of the relationship between the lower critical solution temperature (LCST) of the linear polymer and the volume phase transition temperature (VPTT) of the corresponding hydrogel. Here, the LCST and the onset temperature of linear poly(N-isopropy- lacrylamide-co-N-hydroxymethyl acrylamide) has been determined under pseudo-physiological conditions by cloud point (CP) measurements and by microcalorimetric analysis. The LCSTs, as well as the onset temperatures, determined by the CP method, decrease with increasing the concentration of the polymer solution. On the contrary, microcalorimetric analyses give almost the same values for LCSTs and the onset temperatures regardless of polymer concentration. The VPTT of the hydrogel, determined by the blue dextran method, was found to be closely similar to the LCST of the concentrated polymer solution (10%, w/v), determined by the CP method. In fact, the hydrogel could be considered as a concentrated polymer solution whose concentration could be related to the amount of water retained by the hydrogel. Hydrogel microspheres have been also reported to release diclofenac, a drug model system, in a pulsating way at temperatures slightly below and above the VPTT

Pullulan/Poly(vinyl alcohol) Hydrogels Loaded with Calendula officinalis Extract: Design and In Vitro Evaluation for Wound Healing Applications

The therapeutic efficiency of plant extracts has been limited by their poor pharmaceutical availability. Hydrogels have promising potential to be applied as wound dressings due to their high capacity to absorb exudates and their enhanced performance in loading and releasing plant extracts. In this work, pullulan/poly (vinyl alcohol) (P/PVA) hydrogels were first prepared using an eco-friendly method based on both a covalent and physical cross-linking approach. Then, the hydrogels were loaded with the hydroalcoholic extract of Calendula officinalis by a simple post-loading immersion method. Different loading capacities were investigated in terms of the physico-chemical properties, chemical composition, mechanical properties, and water absorption. The hydrogels exhibited high loading efficiency due to the hydrogen bonding interactions between polymer and extract. The water retention capacity as well as the mechanical properties decreased with the increase in the extract amount in hydrogel. However, higher amounts of extract in the hydrogel improved the bioadhesiveness. The release of extract from hydrogels was controlled by the Fickian diffusion mechanism. Extract-loaded hydrogels expressed high antioxidant activity, reaching 70% DPPH radical scavenging after 15 min immersion in buffer solution at pH 5.5. Additionally, loaded hydrogels showed a high antibacterial activity against Gram-positive and Gram-negative bacteria and were non-cytotoxic against HDFa cells

Bio-Responsive Carriers for Controlled Delivery of Doxorubicin to Cancer Cells

The cellular internalization of drug carriers occurs via different endocytic pathways that ultimately involve the endosomes and the lysosomes, organelles where the pH value drops to 6.0 and 5.0, respectively. We aimed to design and characterize pH/temperature-responsive carriers for the effective delivery of the anti-tumoral drug doxorubicin. To this purpose, poly(N-isopropylacrylamide-co-vinylimidazole) was synthesized as an attractive pH/temperature-sensitive copolymer. Microspheres made of this copolymer, loaded with doxorubicin (MS-DXR), disintegrate in monodisperse nanospheres (NS-DXR) under conditions similar to that found in the bloodstream (pH = 7.4, temperature of 36 °C) releasing a small amount of payload. However, in environments that simulate the endosomal and lysosomal conditions, nanospheres solubilize, releasing the entire amount of drug. We followed the NS-DXR internalization using two cancer cell lines, hepatic carcinoma HepG2 cells and lung adenocarcinoma A549 cells. The data showed that NS-DXR are internalized to a greater extent by HepG2 cells than A549 cells, and this correlated with increased cytotoxicity induced by NS-DXR in HepG2 cells compared with A549 cells. Moreover, NS-DXR particles do not cause hemolysis and erythrocytes aggregation. Administered in vivo, NS-DXR localized in the liver and kidneys of mice, and the loading of DXR into NS resulted in the reduced renal clearance of DXR. In conclusion, the newly developed poly(N-isopropylacrylamide-co-vinyl imidazole) particles are biocompatible and may be introduced as carriers for doxorubicin to hepatic tumors

Dual Cross-Linked Chitosan/PVA Hydrogels Containing Silver Nanoparticles with Antimicrobial Properties

Stable chitosan/PVA-based hydrogels were obtained by combining covalent and physical cross-linking methods. As covalent cross-linkers, epoxy agents with different chain lengths were used, while freeze–thaw cycles were applied for additional physical cross-linking. The chemical structure of the hydrogel was examined by FTIR spectroscopy whereas the morphology was analyzed by SEM, showing well-defined pores with dimensions of around 50 μm in diameter. It was proved that gel fraction and the network morphology were deeply influenced by the synthesis conditions. Chitosan/PVA hydrogel showed a relative high swelling rate, reaching equilibrium in the first hour. The values obtained for the elastic modulus were relatively low (3–30 kPa); as a result, these hydrogels are soft and very flexible, and are ideal candidates for medical applications as wound or oral dressings. In addition, the natural antimicrobial activity of chitosan was enhanced by in situ generation of silver nanoparticles (AgNPs) under UV irradiation. The total amount of Ag from hydrogel was determined by elemental analyses and its crystalline state was confirmed by XRD. The CS/PVA hydrogels entrapped with AgNPs exhibited high inhibitory activity against S. aureus and K. pneumonia. The vitality tests confirmed the lack of cytotoxicity of CS/PVA hydrogels without and with AgNPs

Eco-Friendly Synthesized PVA/Chitosan/Oxalic Acid Nanocomposite Hydrogels Embedding Silver Nanoparticles as Antibacterial Materials

PVA/chitosan (PVA/CS) composite hydrogels incorporating silver nanoparticles (AgNPs) were prepared by double-cross-linked procedures: freeze–thawing and electrostatic interactions. Oxalic acid (OA) was used both for solubilization and ionic cross-linking of CS. AgNPs covered by CS (CS-AgNPs) with an average diameter of 9 nm and 18% silver were obtained in the presence of CS, acting as reducing agent and particle stabilizer. The increase of the number of freeze–thaw cycles, as well as of the PVA:CS and OA:CS ratios, resulted in an increase of the gel fraction and elastic modulus. Practically, the elastic modulus of the hydrogels increased from 3.5 kPa in the absence of OA to 11.6 kPa at a 1:1 OA:CS weight ratio, proving that OA was involved in physical cross-linking. The physicochemical properties were not altered by the addition of CS-AgNPs in low concentration; however, concentrations higher than 3% resulted in low gel fraction and elastic modulus. The amount of silver released from the composite hydrogels is very low (<0.4%), showing that AgNPs were well trapped within the polymeric matrix. The composite hydrogels displayed antimicrobial activity against S. aureus, K. pneumoniae or P. gingivalis. The low cytotoxicity and the antibacterial efficacy of hydrogels recommend them for wound and periodontitis treatment

PVA/Chitosan Thin Films Containing Silver Nanoparticles and Ibuprofen for the Treatment of Periodontal Disease

Local delivery of drugs or antimicrobial agents is a suitable approach in the management of periodontitis when the infection is localized deep in the pockets and does not adequately respond to mechanical debridement and/or systemic antibiotic treatment. In this context, the objective of this study was to prepare new biocomposite films with antimicrobial, anti-inflammatory, and good mechanical properties to be applied in periodontal pockets. The composite film is eco-friendly synthesized from poly(vinyl alcohol) (PVA) cross-linked with oxidized chitosan (OxCS). Silver nanoparticles (AgNps) were inserted during film synthesis by adding freshly chitosan-capped AgNps colloidal solution to the polymer mixture; the addition of AgNps up to 1.44 wt.% improves the physico-chemical properties of the film. The characterization of the films was performed by FT-IR, atomic mass spectrometry, X-ray spectroscopy, and SEM. The films displayed a high swelling ratio (162%), suitable strength (1.46 MPa), and excellent mucoadhesive properties (0.6 N). Then, ibuprofen (IBF) was incorporated within the best film formulation, and the IBF-loaded PVA/OxCS-Ag films could deliver the drug in a sustained manner up to 72 h. The biocomposite films have good antimicrobial properties against representative pathogens for oral cavities. Moreover, the films are biocompatible, as demonstrated by in vitro tests on HDFa cell lines