Nanosilver-Functionalized Hybrid Hydrogels of Carboxymethyl Cellulose/Poly(Vinyl Alcohol) with Antibacterial Activity for Prevention and Therapy of Infections of Diabetic Chronic Wounds.

Diabetic foot ulcers (DFUs) are considered one of the most severe chronic complications of diabetes and can lead to amputation in severe cases. In addition, bacterial infections in diabetic chronic wounds aggravate this scenario by threatening human health. Wound dressings made of polymer matrices with embedded metal nanoparticles can inhibit microorganism growth and promote wound healing, although the current clinical treatments for diabetic chronic wounds remain unsatisfactory. In this view, this research reports the synthesis and characterization of innovative hybrid hydrogels made of carboxymethyl cellulose (CMC) and poly(vinyl alcohol) (PVA) chemically crosslinked by citric acid (CA) functionalized with silver nanoparticles (AgNPs) generated in situ using an eco-friendly aqueous process. The results assessed through comprehensive in vitro and in vivo assays demonstrated that these hybrid polymer hydrogels functionalized with AgNPs possess physicochemical properties, cytocompatibility, hemocompatibility, bioadhesion, antibacterial activity, and biocompatibility suitable for wound dressings to support chronic wound healing process as well as preventing and treating bacterial infections. Hence, it can be envisioned that, with further research and development, these polymer-based hybrid nanoplatforms hold great potential as an important tool for creating a new generation of smart dressings for treating chronic diabetic wounds and opportunistic bacterial infections.

Carboxymethylcellulose biofunctionalized ternary quantum dots for subcellular-targeted brain cancer nanotheranostics.

Among the most lethal forms of cancer, malignant brain tumors persist as one of the greatest challenges faced by oncologists, where nanotechnology-driven theranostics can play a critical role in developing novel polymer-based supramolecular nanoarchitectures with multifunctional and multi-modal characteristics to fight cancer. However, it is virtually a consensus that, besides the complexity of active delivering anticancer drugs by the nanocarriers to the tumor site, the current evaluation methods primarily relying on in vitro assays and in vivo animal models have been accounted for the low translational effectiveness to clinical applications. In this view, the chick chorioallantoic membrane (CAM) assay has been increasingly recognized as one of the best preclinical models to study the effects of anticancer drugs on the tumor microenvironment (TME). Thus, in this study, we designed, characterized, and developed novel hybrid nanostructures encompassing chemically functionalized carboxymethylcellulose (CMC) with mitochondria-targeting pro-apoptotic peptide (KLA) and cell-penetrating moiety (cysteine, CYS) with fluorescent inorganic semiconductor (Ag-In-S, AIS) for simultaneously bioimaging and inducing glioblastoma cancer cell (U-87 MG, GBM) death. The results demonstrated that the CMC-peptide macromolecules produced supramolecular vesicle-like nanostructures with aqueous colloidal stability suitable as nanocarriers for passive and active targeting of cancer tumors. The optical properties and physicochemical features of the nanoconjugates confirmed their suitability as photoluminescent nanoprobes for cell bioimaging and intracellular tracking. Moreover, the results in vitro demonstrated a notable killing activity towards GBM cells of cysteine-bearing CMC conjugates coupled with pro-apoptotic KLA peptides. More importantly, compared to doxorubicin (DOX), a model anticancer drug in chemotherapy that is highly toxic, these innovative nanohybrids nanoconjugates displayed higher lethality against U-87 MG cancer cells. In vivo CAM assays validated these findings where the nanohybrids demonstrated a significant reduction of GBM tumor progression (41% area) and evidenced an antiangiogenic activity. These results pave the way for developing polymer-based hybrid nanoarchitectonics applied as targeted multifunctional theranostics for simultaneous imaging and therapy against glioblastoma while possibly reducing the systemic toxicity and side-effects of conventional anticancer chemotherapeutic agents.

Dual-functional supramolecular nanohybrids of quantum dot/biopolymer/chemotherapeutic drug for bioimaging and killing brain cancer cells in vitro.

Glioblastoma (GBM) is the utmost aggressive and lethal primary brain cancer, which has a poor prognosis and remains virtually incurable. Nanomedicine with emerging disruptive nanotechnology alternatives, including designed supramolecular nanohybrids has excellent potential as multimodal tools against cancer by combining nanomaterials, biomacromolecules, and drugs. Thus, we developed and constructed for the first time quantum dot-biopolymer-drug nanohybrids based on host-guest chemistry for simultaneous bioimaging, targeting, and anti-cancer drug delivery against GBM cells in vitro. ZnS fluorescent quantum dots (ZnS-QDs) were produced using chemically modified polysaccharide, carboxymethylcellulose (CMC), as water-soluble capping ligand and biofunctional layer via a facile one-step eco-friendly aqueous colloidal process at room temperature and physiological pH. These hybrid inorganic-organic nanocolloids (ZnS@CMC) were electrostatically conjugated with doxorubicin (DOX) anti-cancer drug forming innovative supramolecular complexes (ZnS@CMC-DOX) for amalgamating bioimaging and killing cancer cells. These nanoconjugates were characterized regarding their optical and physicochemical properties combined with morphological and structural features. The cytocompatibility was evaluated by MTT assay using healthy and GBM cells. The results showed that ultra-small ZnS-QDs were expertly produced uniform nanocolloids (average size = 3.6 nm). They demonstrated photoluminescence emission within the visible range of spectra. The cell viability results in vitro showed no cytotoxicity of ZnS@CMC nanohybrids towards both cell types. In summary, the novelty of this research relies on using a nanotheranostic strategy for developing ZnS@CMC-DOX nanohybrids with supramolecular vesicle-like structures. They behaved simultaneously as active fluorescent nanoprobes and nanocarriers with modulated drug release for bioimaging and killing malignant glioma cells proving the high potential for applications in cancer nanomedicine.

Bioengineered carboxymethyl cellulose-doxorubicin prodrug hydrogels for topical chemotherapy of melanoma skin cancer.

Melanoma is the most aggressive type of skin cancer with high rates of mortality. Despite encouraging advances demonstrated by anticancer drug carriers in recent years, developing ideal drug delivery systems to target tumor microenvironment by overcoming physiological barriers and chemotherapy side effects still remain intimidating challenges. Herein, we designed and developed a novel carbohydrate-based prodrug composed of carboxymethylcellulose (CMC) polymer bioconjugated with anticancer drug doxorubicin hydrochloride (DOX) by covalent amide bonds and crosslinked with citric acid for producing advanced hydrogels. The results demonstrated the effect of CMC hydrogel network structure with distinct degree of substitution of carboxymethyl groups of the cellulose backbone regarding to the process of bioconjugation and on tailoring the DOX release kinetics in vitro and the cytotoxicity towards melanoma cancer cells in vitro. To this end, an innovative platform was developed based on polysaccharide-drug hydrogels offering promising perspectives for skin disease applications associated with topical chemotherapy of melanoma.

Superabsorbent crosslinked carboxymethyl cellulose-PEG hydrogels for potential wound dressing applications.

This study focused on the synthesis and comprehensive characterization of environmentally friendly hydrogel membranes based on carboxymethyl cellulose (CMC) for wound dressing and skin repair substitutes. These new CMC hydrogels were prepared with two degrees of functionalization (DS=0.77 and 1.22) and chemically crosslinked with citric acid (CA) for tuning their properties. Additionally, CMC-based hybrids were prepared by blending with polyethylene glycol (PEG, 10wt.%). The results demonstrated that superabsorbent hydrogels (SAP) were produced with swelling degree typically ranging from 100% to 5000%, which was significantly dependent on the concentration of CA crosslinker and the addition of PEG as network modifier. The spectroscopical characterizations indicated that the mechanism of CA crosslinking was mostly associated with the chemical reaction with CMC hydroxyl groups and that PEG played an important role on the formation of a hybrid polymeric network. These hydrogels presented very distinct morphological features depended on the degree of crosslinking and the surface nanomechanical properties (e.g., elastic moduli) were drastically affected (from approximately 0.08GPa to 2.0GPa) due to the formation of CMC-PEG hybrid nanostructures. These CMC-based hydrogels were cytocompatible considering the in vitro cell viability responses of over 95% towards human embryonic kidney cells (HEK293T) used as model cell line.

Eco-friendly and biocompatible cross-linked carboxymethylcellulose hydrogels as adsorbents for the removal of organic dye pollutants for environmental applications.

In this study, new eco-friendly hydrogel adsorbents were synthesized based on carboxymethylcellulose (CMC, degree of substitution [DS] = 0.7) chemically cross-linked with citric acid (CA) using a green process in aqueous solution and applied for the adsorption of methylene blue (MB). Spectroscopic analyses demonstrated the mechanism of cross-linking through the reaction of hydroxyl functional groups from CMC with CA. These CMC hydrogels showed very distinct morphological features dependent on the extension of cross-linking and their nanomechanical properties were drastically increased by approximately 300% after cross-linking with 20% CA (e.g. elastic moduli from 80 ± 15 to 270 ± 50 MPa). Moreover, they were biocompatible using an in vitro cell viability assay in contact with human osteosarcoma-derived cells (SAOS) for 24 h. These CMC-based hydrogels exhibited adsorption efficiency above 90% (24 h) and maximum removal capacity of MB from 5 to 25 mg g-1 depending on the dye concentration (from 100 to 500 mg L-1), which was used as the model cationic organic pollutant. The adsorption of process of MB was well-fit to the pseudo-second-order kinetics model. The desorption of MB by immersion in KCl solution (3 mol L-1, 24 h) showed a typical recovery efficiency of over 60% with conceivable reuse of these CMC-based hydrogels. Conversely, CMC hydrogels repelled methyl orange dye used as model anionic pollutant, proving the mechanism of adsorption by the formation of charged polyelectrolyte/dye complexes.

Glycol chitosan/nanohydroxyapatite biocomposites for potential bone tissue engineering and regenerative medicine.

In the last few decades, research on biocomposite nanomaterials has grown exponentially due to the global demand for novel solutions in bone tissue engineering and repair. In the present study, it is reported the design and synthesis of biocomposites based on glycol chitosan (GLY-CHI) matrices incorporated with nano-hydroxyapatite particles (nHA) produced via an eco-friendly chemical colloidal process in water media followed by solvent casting and evaporation methods at room temperature. The structure, morphology, and crystallinity of the components and biocomposites were extensively characterized by light microscopy (LM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), wavelength dispersive X-ray fluorescence spectroscopy (WD-XRF), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and X-ray micro-computed tomography analysis (µCT). Furthermore, cytotoxicity and cell viability tests were performed on three cell lines using a 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyl tetrazolium bromide (MTT) assay, an alkaline phosphatase (ALP) activity test, and LIVE/DEAD® assays. The results demonstrated that the GLY-CHI ligand played a major role in the nucleation, growth and colloidal stabilization of calcium phosphate particles at nanoscale dimensions with a narrow distribution and average size of 74±15nm. The FTIR spectroscopy associated with the XRD results indicated that nanosized hydroxyapatite (nHA) was the predominant calcium phosphate phase produced in the colloidal processing route. In addition, the X-ray micro-CT analysis of the nanocomposite membranes showed that nHA particles were homogenously dispersed in the glycol-chitosan polymeric matrix. Moreover, according to the in vitro bioassays, the biocomposites showed an adequate cell viability response and non-cytotoxic behavior toward osteoblastic-like (SAOS) and embryonic cell lines (HEK293T). Finally, the results of osteogenic differentiation tests demonstrated that the nHA/GLY-CHI composites are osteoinductive for human bone marrow mesenchymal stem cells (HBMS), which can be envisioned for prospective use in tissue engineering (e.g., bone, cartilage and periodontal) applications.

Niobium-Doped Hydroxyapatite Bioceramics: Synthesis, Characterization and In Vitro Cytocompatibility.

Doping calcium phosphates with ionic species can play an important role in biological responses promoting alkaline phosphatase activity, and, therefore inducing the generation of new bone. Thus, in this study, the synthesis of niobium-doped hydroxyapatite (Nb-HA) nanosize particles obtained by the precipitation process in aqueous media followed by thermal treatment is presented. The bioceramics were extensively characterized by X-ray diffraction, wavelength dispersive X-ray fluorescence spectrometry, Fourier transform infrared spectroscopy, scanning electron microscopy/energy dispersive X-ray spectroscopy analysis, transmission electron microscopy, atomic force microscopy and thermal analysis regarding their chemical composition, structure and morphology. The results showed that the precipitate dried at 110 °C was composed of amorphous calcium phosphate and HA, with polidisperse particles ranging from micro to nano dimensions. After the thermal treatment at 900 °C, the bioceramic system evolved predominantly to HA crystalline phase, with evident features of particle sintering and reduction of surface area. Moreover, the addition of 10 mol% of niobium salt precursor during the synthesis indicated the complete incorporation of the Nb(V) species in the HA crystals with detectable changes in the original lattice parameters. Furthermore, the incorporation of Nb ions caused a significant refinement on the average particle size of HA. Finally, the preliminary cytocompatibility response of the biomaterials was accessed by human osteoblast cell culture using MTT and resazurin assays, which demonstrated no cytotoxicity of the Nb-alloyed hydroxyapatite. Thus, these findings seem promising for developing innovative Nb-doped calcium phosphates as artificial biomaterials for potential use in bone replacements and repair.