Carboxymethylcellulose hydrogels crosslinked with keratin nanoparticles for efficient prednisolone delivery.

Carboxymethylcellulose (CMC) and keratin nanoparticle (KNP) hydrogels were obtained, characterized, and applied as drug delivery systems (DDSs) for the first time. Lyophilized CMC/KNP mixtures containing 10, 25, and 50 wt% of KNPs were kept at 170 °C for 90 min to crosslink CMC chains through a solid-state reaction with the KNPs. The hydrogels were characterized by infrared spectroscopy, thermal analyses, X-ray diffraction, mechanical measurements, and scanning electron microscopy. The infrared spectra indicated the formation of ester and amide linkages between crosslinked CMC and KNPs. The elastic modulus of the hydrogel containing 10 wt% KNPs was 2-fold higher than that of the hydrogel containing 50 wt% KNPs. The mechanical properties influenced the hydrogel stability and water uptake. The anti-inflammatory prednisolone (PRED) drug was incorporated into the hydrogels, and the release mechanism was investigated. The hydrogels supported PRED release by drug desorption for approximately 360 h. A sustained release mechanism was achieved. The CMC/KNP and CMC/KNP/PRED hydrogels were cytocompatible toward mammalian cells. The CMC/KNP/PRED set imparted the highest cell viability after 7 days of incubation. This study showed a straightforward procedure to create DDSs (chemically crosslinked) based on polysaccharides and proteins for efficient PRED delivery.

Nanofibrous silica microparticles/polymer hybrid aerogels for sustained delivery of poorly water-soluble camptothecin.

The surface functionalization of nanoporous silica materials with chemical agents opens up numerous possibilities, including improvement in the materials' ability to carry high payloads of drugs. In this study, KCC-1 nanofibrous silica microparticles are functionalized with methyl groups and then combined with poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) to produce hybrid aerogels that can deliver a poorly water-soluble anticancer drug. The synthetic steps involve freeze-drying a polymer solution of PVA and PAA that contains methyl-modified KCC-1 microparticles and then cross-linking the two polymers via a solid-state reaction. Benefiting from the incorporated methyl-modified KCC-1 microparticles, the hybrid aerogels can load and deliver a payload of camptothecin (CPT), an anticancer drug with antitumor activity but limited clinical application due to its hydrophobicity. The aerogels also show a sustained release of CPT for more than two weeks. The drug release profile can further be tuned by varying the relative amounts of PVA, PAA, and methyl-modified KCC-1. The aerogels are biocompatible to healthy cells, such as immortalized human epithelial (HaCaT), African green monkey kidney (Vero) and murine fibroblast (L929) cells. When loaded with CPT, they show potent antitumor activity against HeLa (HPV18-positive), SiHa (HPV16-positive) and C33A (HPV-negative) cancer cells, significantly inhibiting cell growth.

Designing hybrid materials with multifunctional interfaces for wound dressing, electrocatalysis, and chemical separation.

An infinite number of possibilities can emerge from the combination of phases in hybrid systems. Interfacing phases is a strategy to obtain a set of properties in one system that are beyond the abilities of single phases. Herein, the progress in materials science exploring hybrid systems are discussed from the point of view of three important applications: wound dressing; electrocatalysis; and chemical separation. These three unrelated applications exemplify the broad impact of hybrid materials, which can be coherently designed to achieve outstanding performance. Many inspiring works have been published in the last few years, remodeling the edges of human knowledge on hybrid materials. However, the challenges in the coherent design seem to rely on the development of synthetic processes to achieve stronger integration among the phases in a hybrid material.

Cellulose nanowhiskers decorated with silver nanoparticles as an additive to antibacterial polymers membranes fabricated by electrospinning.

Antimicrobial films based on distinct polymer matrices, poly (vinyl alcohol) (PVA) or poly (N-isopropylacrylamide) (PNIPAAm), and silver nanoparticles (AgNPs) immobilized onto cellulose nanowhiskers (CWs) were successfully prepared by either casting or electrospinning. CWs were first functionalized with carboxylate groups (labeled as CWSAc) and later they were immersed in a silver nitrate solution (AgNO3). After Ag+ ions anchored in the COO- groups are chemically reduced to produce AgNPs. The CWSAc/AgNPs biological activity was evaluated against Staphylococcus aureus (S. aureus), Bacillus Subtilis (B. subtilis), Escherichia coli (E. coli), and Candida albicans (C. albicans). The materials were more effective against C. albicans that showed a MIC of 15.6 µg/mL. In the process of AgNPs synthesis, the activity of the stabilizing agent (gelatin) and concentration of precursor and reducing agents were evaluated. The synthesized polymeric films displayed good antimicrobial activity against S. aureus, E. coli, and Pseudomonas aeruginosa (P. aeruginosa) bacteria. The PVA films with CWSAc/AgNPs showed diameter of the inhibition halo of up to 11 mm. The results obtained displayed that the films obtained have a potential application to be used in different fields such as packaging, membrane filtration, wound dressing, clothing and in different biomedical applications.

Mechanically improved polyvinyl alcohol-composite films using modified cellulose nanowhiskers as nano-reinforcement.

Cellulose nanowhiskers (CWs) extracted from cotton fibers were successfully modified with distinct anhydrides structures and used as additives in poly(vinyl alcohol) (PVA) nanocomposite films. The surface modification of CWs was performed with maleic, succinic, acetic or phthalic anhydride to compare the interaction and action the carboxylic groups into PVA films and how these groups influence in mechanical properties of the nanocomposites. CWs presented a high degree of crystallinity and good dispersion in water, with average length at the nanoscale. The addition of specific amounts (3, 6 and 9 wt.%) of modified-CWs increased up to 4.4 times the storage modulus (PVA88-CWSA 9 wt.%), as observed from dynamic mechanical analysis (DMA), compared to the bare PVA films. A significant increase in mechanical properties such as tensile strength, elastic modulus, and elongation at break showed a close relationship to the amount and chemical surface characteristics of CWs added, suggesting that these modified-CWs could be explored as reinforcement additives in PVA films.

Multifunctional hybrid aerogels: hyperbranched polymer-trapped mesoporous silica nanoparticles for sustained and prolonged drug release.

In this study, we show the synthesis of novel hybrid organic-inorganic aerogel materials with one-dimensionally aligned pores and demonstrate their use as sustained and prolonged release systems for a hydrophobic drug. The materials are synthesized by trapping mesoporous silica nanoparticles within a hyperbranched polymer network made from poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA). The synthetic method involves dispersing mesoporous silica nanoparticles in a polymer solution, then freeze-drying the solution, and finally subjecting the resulting materials to high temperature to activate a solid-state condensation reaction between PVA and PAA. Before trapping the mesoporous silica nanoparticles within the hyperbranched polymeric network, their pores are decorated with hydrophobic groups so that they can serve as good host materials for hydrophobic drugs. The potential application of the hybrid aerogels as drug carriers is demonstrated using the hydrophobic, anti-inflammatory agent dexamethasone (DEX) as a model drug. Due to their hydrophobic pores, the hybrid aerogels show excellent drug loading capacity for DEX, with an encapsulation efficiency higher than 75%. Furthermore, the release pattern of the payloads of DEX encapsulated in the aerogels is highly tailorable (i.e., it can be made faster or slower, as needed) simply by varying the PVA-to-PAA weight ratio in the precursors, and thus the 3-dimensional (3-D) structures of the cross-linked polymers in them. The materials also show sustained drug release, for over 50 days or more. In addition, the aerogels are biocompatible, as demonstrated with Vero cells, and greatly promote the cell proliferation of L929 fibroblasts. Also, the nanoparticles functionalized with quaternary groups and dispersed within the aerogels display bactericidal activity against E. coli, S. aureus, B. subtilis, and P. aeruginosa. These new hybrid aerogels can, thus, be highly appealing biomaterials for sustained and prolonged drug release, such as wound dressing systems.

Hybrid Materials and Nanocomposites as Multifunctional Biomaterials.

This review article provides an overview of hybrid and nanocomposite materials used as biomaterials in nanomedicine, focusing on applications in controlled drug delivery, tissue engineering, biosensors and theranostic systems. Special emphasis is placed on the importance of tuning the properties of nanocomposites, which can be achieved by choosing appropriate synthetic methods and seeking synergy among different types of materials, particularly exploiting their nanoscale nature. The challenges in fabrication for the nanocomposites are highlighted by classifying them as those comprising solely inorganic phases (inorganic/inorganic hybrids), organic phases (organic/organic hybrids) and both types of phases (organic/inorganic hybrids). A variety of examples are given for applications from the recent literature, from which one may infer that significant developments for effective use of hybrid materials require a delicate balance among structure, biocompatibility, and stability.

Advanced fibroblast proliferation inhibition for biocompatible coating by electrostatic layer-by-layer assemblies of heparin and chitosan derivatives.

Heparin and different chitosan derivatives were applied to produce stable electrostatic layer-by-layer assemblies and further used as coating technique to inhibit natural inflammatory response to implants. Heparin was assembled with chitosan and N-methylated chitosan derivatives, namely N,N-dimethyl chitosan (DMC) and N,N,N-trimethyl chitosan (TMC), by dipping method. DMC and TMC (chitosan derivatives) were synthesized and characterized before LbL assembly. Ellipsometry, quartz crystal microbalance (QCM-D), and contact angle were used to demonstrate the deposition of polyelectrolyte multilayers onto silicon wafers using polyelectrolyte solutions with different ionic strength. The biological properties of these films were evaluated by cell culture assays using NIH/3T3 fibroblast cells. LbL assemblies of Heparin and chitosan derivatives showed to be biocompatible, and at the same time they strongly hinder the proliferation speed of fibroblasts up to 40-fold factors. Therefore, the multilayers prepared from heparin and chitosan derivatives have good features to be used as an alternative coating treatment for biomedical implants with reduced body rejection properties.

Preparation and cytotoxicity of N-modified chitosan nanoparticles applied in curcumin delivery.

Nanoparticles (NPs) based on N,N-dimethyl chitosan (DMC) and N,N,N-trimethyl chitosan (TMC), physical crosslinked with sodium tripolyphosphate (TPP) were successful obtained, using water/benzyl alcohol emulsion system. NPs morphologies were evaluated by Scanning Electron Microscopy and Transmission Electron Microscopy. NPs were characterized by Infrared Spectroscopy (FTIR), Thermogravimetric Analysis, Zeta Potential, Differential Scanning Calorimetry and Wide-angle X-ray Scattering. Curcumin (CUR) was loaded onto NPs and controlled release studies were evaluated in simulated intestinal fluid and in simulated gastric fluid. Cytotoxicity assays showed only loaded TMC/TPP particles containing CUR were slightly cytotoxic on human cervical tumor cells (SiHa cells), concerning unloaded TMC/TPP particles. Conversely, loaded NPs (TMC/TPP/CUR and DMC/TPP/CUR), especially TMC/TPP/CUR sample presented greater biocompatibility toward healthy VERO cells than unloaded NPs (TMC/TPP and DMC/TPP).

Extent of shielding by counterions determines the bactericidal activity of N,N,N-trimethyl chitosan salts.

In this study, we show that the bactericidal activity of quaternized chitosans (TMCs) with sulfate, acetate, and halide counterions against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) correlates with the "availability" of N-quaternized groups [-(+)N(CH3)3] in the TMCs backbones. N,N,N-trimethyl chitosan sulfate (TMCS) and N,N,N-trimethyl chitosan acetate (TMCAc) displayed the highest activities, probably due to their delocalized π system. Among TMCs with halide counterions, activity was higher for N,N,N-trimethyl chitosan chloride (TMCCl), whereas N,N,N-trimethyl chitosan iodide (TMCI) and N,N,N-trimethyl chitosan bromide (TMCBr) exhibited lower, similar values to each other. This is consistent with the shielding of -(+)N(CH3)3 groups inferred from chemical shifts for halide counterions in (1)HNMR spectra. We also demonstrate that TMCs with distinct bactericidal activities can be classified according to their vibrational spectra using principal component analysis. Taken together, these physicochemical characterization approaches represent a predictive tool for the bactericidal activity of chitosan derivatives.

Polyelectrolyte complex containing silver nanoparticles with antitumor property on Caco-2 colon cancer cells.

Polyelectrolyte complex (beads) based on N,N,N-trimethyl chitosan/alginate was successful obtained and silver nanoparticles (AgNPs) were loaded within beads. In vitro cytotoxicity assays using beads/silver nanoparticles (beads/AgNPs) provided results, indicating that this material significantly inhibited the growth of colon cancer cells (Caco-2). In vitro release studies showed that the beads stabilized AgNPs and repressed Ag(0) oxidation under gastric conditions (pH 2.0). On the other hand, at physiological condition (pH 7.4) the beads/AgNPs released 3.3 µg of Ag(+) per each beads milligram. These studies showed that the concentration of Ag(+) released (3.3 µg) was cytotoxic for the Caco-2 cells and was not cytotoxic on healthy VERO cells. This result opens new perspectives for the manufacture of biomaterials based on beads/AgNPs with anti-tumor properties.

N,N-Dimethyl chitosan/heparin polyelectrolyte complex vehicle for efficient heparin delivery.

Polysaccharide-based device for oral delivery of heparin (HP) was successfully prepared. Previously synthesized N,N-dimethyl chitosan (DMC) (86% dimethylated by (1)H NMR spectroscopy) was complexed with HP by mixing HP and DMC aqueous solutions (both at pH 3.0). The polyelectrolyte complex (PEC) obtention was confirmed by infrared spectroscopy (FTIR), thermogravimetric analysis (TGA/DTG) and wide-angle X-ray scattering (WAXS). In vitro controlled release assays of HP from PEC were investigated in the simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). The PEC efficiently protected the HP in SGF condition in which HP is degraded. On the other hand, in SIF PEC promoted the releasing of 80 ± 1.5% of loaded HP. The promissory results indicated that the PEC based on DMC/HP presented potential as drug-carrier matrix, since biological activity of HP was improved at pH close to physiological condition.

Shielding effect of 'surface ion pairs' on physicochemical and bactericidal properties of N,N,N-trimethyl chitosan salts.

Different methodologies were employed in this study to synthesize N,N,N-trimethyl chitosan salts (TMC). TMC free of O-methylation and with partial O-methylation were obtained and characterized through 1H nuclear magnetic resonance, wide angle X-ray scattering, scanning electron microscopy coupled with X-ray energy dispersive spectroscopy, and thermogravimetric analysis. It was verified that the dialysis process allowed the removal of 'surface ion pairs' on TMC salt structure, increasing the mobility of TMC chains. The surface ion pairs considerably increased the material crystallinity, this property being independent of the used synthesis methodology. Biological tests showed that after dialysis, TMC salts free of 'surface ion pairs' kill Escherichia coli in only 6h of incubation. So, the increase in the mobility of dialyzed TMC chains allowed a strong interaction with the cell envelope and the good bactericidal activity of TMC was enhanced.

Antimicrobial activity of chitosan derivatives containing N-quaternized moieties in its backbone: a review.

Chitosan, which is derived from a deacetylation reaction of chitin, has attractive antimicrobial activity. However, chitosan applications as a biocide are only effective in acidic medium due to its low solubility in neutral and basic conditions. Also, the positive charges carried by the protonated amine groups of chitosan (in acidic conditions) that are the driving force for its solubilization are also associated with its antimicrobial activity. Therefore, chemical modifications of chitosan are required to enhance its solubility and broaden the spectrum of its applications, including as biocide. Quaternization on the nitrogen atom of chitosan is the most used route to render water-soluble chitosan-derivatives, especially at physiological pH conditions. Recent reports in the literature demonstrate that such chitosan-derivatives present excellent antimicrobial activity due to permanent positive charge on nitrogen atoms side-bonded to the polymer backbone. This review presents some relevant work regarding the use of quaternized chitosan-derivatives obtained by different synthetic paths in applications as antimicrobial agents.

Synthesis, characterization, and cytotoxicity of TMC-graft-poly(vinyl alcohol) copolymers.

N-trimethyl chitosan-graft-poly(vinyl alcohol) (TMC-g-PVA) copolymers were prepared. The grafting reactions were conducted in water changing the feed ratios of poly(vinyl alcohol)/6-O-succinate-N-trimethyl chitosan (PVA/STMC). The structure of TMC-g-PVA copolymers was characterized through (1)H NMR spectroscopy, thermogravimetric analysis (TGA/DTG), wide-angle X-ray scattering (WAXS) and scanning electron microscopy (SEM). The quaternization degree (DQ) and substitution degree (DS) of N-trimethyl chitosan (TMC) and 6-O-succinate-N-trimethyl chitosan (STMC) were determined by (1)H NMR, being the spectroscopy 14.0 and 5.5mol-% found, respectively. The viability of HCT-116 cancerous cells was investigated at different concentrations. The effect of PVA/STMC ratios on the cytotoxicity of the TMC-g-PVA copolymers was examined and the CC50 values determined for every case.

Antiadhesive and antibacterial multilayer films via layer-by-layer assembly of TMC/heparin complexes.

N-Trimethyl chitosan (TMC), an antibacterial agent, and heparin (HP), an antiadhesive biopolymer, were alternately deposited on modified polystyrene films, as substrates, to built antiadhesive and antibacterial multilayer films. The properties of the multilayer films were investigated by Fourier transform infrared spectroscopy, atomic force microscopy, scanning electron microscopy, and Kelvin force microscopy. In vitro studies of controlled release of HP were evaluated in simulated intestinal fluid and simulated gastric fluid. The initial adhesion test of E. coli on multilayer films surface showed effective antiadhesive properties. The in vitro antibacterial test indicated that the multilayer films of TMC/HP based on TMC80 can kill the E. coli bacteria. Therefore, antiadhesive and antibacterial multilayer films may have good potential for coatings and surface modification of biomedical applications.