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Abstract The aim of this study was to develop an effective cell sheet translocation method using a cell adhesive and temperature-responsive hydroxybutyl chitosan hydrogel (HBC). The polydopamine (PD)-coated HBC hydrogels were prepared by the dopamine self-polymerization on the surface of HBC hydrogel with different coating time, termed as P30, P60 and P120, respectively. Gelling property of HBC was not affected by PD coating. The PD-coated HBC hydrogels promoted the attachment and proliferation of mouse fibroblast cells (L929) and human umbilical vein endothelial cells (HUVECs), and allowed formation of monolayer cell sheet. In vitro translocation of HUVECs sheet could be obtained successively through phase transition of PD coated HBC hydrogel from gel to sol, and the cells sheet transferred from P30 hydrogel to a round cell coverglass maintained relatively complete monolayer and normal cell morphology. The results showed that P30 hydrogel has the potential to be used for cell transplantation therapy. Highlights • The PD-coated hydrogels emerged a special porous structure with a small surface pore size. • The PD-coated hydrogels had phase transition between gels-sols. • The L929 and HUVECs cells could attach and proliferate in the surface of the PD-coated hydrogels. • The transferred cells sheet maintained relatively complete monolayer and normal cell morphology. [ABSTRACT FROM AUTHOR]

Chitosan based nanogels with pH/redox sensitivities tunable to stepwise response to intracellular delivery kinetics were developed. The nanogels were simply constructed by ionic gelation first, between O-Carboxymethyl-chitosan (CMCS) and thiolated chitosan (TCS), and then oxidation to form disulfide bonds for CMCS-TCS nanogels (CTNGs). Doxorubicin loaded nanogels (DOX/CTNGs) exhibited desirable stability under physiological pH with a mean size of 150.5 nm, and quickly aggregated at pH 5.5 (mimic endo/lysosomes) due to protonation of the carboxyl groups on CMCS. DOX/CTNGs would maintain their TCS skeleton in acidic pH and compromised as treated with 10 mM glutathione (mimic cytosol). In agreement with the structural variation, release of DOX was dramatically enhanced by the synergetic effects of acidic pH and reductive potential. Stepwise responses to intracellular delivery kinetics were evidenced by laser confocal images showing that DOX/CTNGs underwent efficient cellular internalization through endocytosis, endo/lysomse escape via self-precipitation, cleavage of disulfide linkage in cytosol and disintegration in nucleus, achieving enhanced nuclear delivery and rapid release of doxorubicin. DOX/CTNGs exerted comparable or higher anticancer efficacies than that of free DOX against hela cells. The simple construction of the nanogels and their capacity of enhancing anticancer activities of DOX are potential for translational applications in cancer chemotherapy. [ABSTRACT FROM AUTHOR]

A novel intelligent nanocarrier with pH and redox sensitivities was developed based on Carboxymethyl-chitosan (CMCS) and thioglycolic acid conjugated chitosan (TCS) to provide precise spatiotemporal control for efficient intracellular delivery. Doxorubicin (DOX) loaded nanocarriers (DOX/CMCS-TCS NPs) were simply prepared by ionic gelation and then oxidation crosslink. The nanocarriers exhibited decent stability at pH 7.4 for up to 3 days and underwent aggregation under acidic pH (5.5) due to protonation of the carboxyl groups on CMCS. The TCS skeleton was stable at pH 5.5 (mimic endo/lysosomes) but disintegrated in the presence of 10 mM glutathione (GSH) at pH 7.4 (mimic cytosol). In vitro DOX release from DOX/CMCS-TCS NPs was enhanced at pH 5.5 compared with physiological condition, with 64.2% and 31.6% DOX released in 2 h, respectively. While 85.2% of DOX was released within 2 h as treated with 10 mM GSH, suggesting the release was closely associated with structural disintegration of nanocarriers. The maximum release of DOX was obtained at 10 mM GSH and pH 5.5 with 92.3% of DOX released in 5 h. Confocal laser scanning microscopy observation indicated that DOX/CMCS-TCS NPs efficiently escaped from endo/lysosomes within 1 h incubation with MCF-7 cells and gave the best performance in delivering DOX into nucleus in 2 h. Anticancer activity assay revealed that DOX/CMCS-TCS NPs had comparable or even better inhibition of cell viability at high drug concentrations than free DOX, with the IC 50 of 0.6 μg/mL following 48 h incubation. In summary, the simply constructed DOX/CMCS-TCS NPs could not only respond to intracellular delivery temporally, they also achieve rapid release spatially in nucleus, which provide a precise spatiotemporal control of drug delivery for cancer therapy. [ABSTRACT FROM AUTHOR]

Intestinal epithelium is a major barrier limiting the absorption of oral insulin owing to the presence of intercellular tight junctions (TJs). Previous studies proved that carboxymethyl chitosan/chitosan-nanoparticles (CMCS/CS-NPs) exhibited surface charge depending promotion of intestinal absorption. This study further confirmed the better performances of insulin:CMCS/CS-NPs(−) in enhancing epithelial permeation, increasing bioavailability and extending blood duration of insulin than insulin:CMCS/CS-NPs(+). Immunohistochemistry sections found that TJs on jejunum epithelium completely disappeared in insulin:CMCS/CS-NPs(−) group, partially existed in insulin:CMCS/CS-NPs(+) group and appeared no change in control. Surface charges of CMCS/CS-NPs triggered intestinal epithelial TJs opening through different mechanisms. Although a down-regulation of TJs protein claudin-4 was detected in both nanoparticles groups, for phosphorylated claudin-4, the activating form, whose down-regulation occurred only in insulin:CMCS/CS-NPs(−) group. Counting upon synergetic effects of Ca 2+ deprivation from adherens junctions and claudin-4 dephosphorylation and degradation, CMCS/CS-NPs(−) triggered more extensive disintegration of TJs and stronger paracellular permeability than the positive. [ABSTRACT FROM AUTHOR]

The gelling behaviors of thiolated chitosan (TCS) in alkaline condition were investigated. Thioglycolic acid was conjugated onto chitosan backbone through amide bond formation. The variations of thiol group content were monitored in presence of H 2 O 2 or different pH values (pH 7.0, 8.0, 9.0) in dialysis mode. Different from the decreasing thiol group content upon time in acidic condition, increasing amount of thiol groups was detected in alkaline pH during 120 min dialysis attributed to alkaline hydrolysis of intra-molecular disulfide bonds. The extent of which was larger at higher pH values. Higher degree of thiolation, thiomer concentration or pH values promoted gelation of TCS. Entanglement and coagulation of chitosan molecule chains and re-arrangement of disulfide bonds acted closely and dynamically in the gelation process. Disulfide bonds, especially inter-molecular type, are formed by synergetic effects of thiol/disulfide interchange and thiol/thiol oxidation reactions. TCS coated vascular stent displayed wave-like microstructure of parallel ridges and grooves, which favored HUVECs adhesion and proliferation. The biocompatibility, peculiar morphology and thiol moieties of TCS as stent coating material appear application potential for vascular stent. [ABSTRACT FROM AUTHOR]

To evaluate the potential of N-acetylated chitosan microspheres used as a chemoembolic agent in vivo and in vitro. Calibrated spherical chitosan microspheres (CMs) were prepared via Water-in-Oil emulsification method and CMs were acetylated (ACMs). The swelling rate of CMs was greatly affected by pH than that of ACMs and both of them affected by temperature. Microspheres with excellent thermal stability demonstrated controllable degradation in lysozyme solution. Doxorubicin was released from microspheres in vitro and exhibited excellent control release profile. ACMs caused hemolysis less than CMs (<5% of the time). Co-culture with mouse embryo fibroblasts revealed that microspheres have non-cytotoxic nature. Microspheres planted in a rat gluteal muscle demonstrated that it were biodegradable and biocompatible. ACMs were performed in rabbit ear embolization model and ischemic necrosis on ear was visible due to the vascular occlusion after 15 days. Acetylated chitosan microspheres could be used as potential biocompatible and biodegradable embolic agents. [ABSTRACT FROM AUTHOR]

The aim was to investigate the potential of chitosan microspheres (CMs) with different acetylation using as a chemoembolic agent. Chitosan microspheres (CMs) were prepared via water-in-oil (W/O) emulsification cross-linking method, and acetylated chitosan microspheres (ACMs) were obtained by acetylation of CMs. Next, we characterized the morphology, size, composition and degrees of deacetylation using scanning electron microscopy (TEM), dynamic laser light scattering (DLS), and Fourier transform infrared spectrometer (FTIR). All microspheres had smooth surfaces and good mechanical flexibility, and all could pass through a 5F catheter. The swelling rate (SR) of CMs decreased significantly with the increase of pH (4.0–10.0) but ACMs did not change under the same conditions. Protein absorption assays suggested that albumin was more greatly adsorbed on CMs than on ACMs. Furthermore, CMs caused more blood clots than ACMs. ACMs caused hemolysis less than CMs (<5% of the time). Data indicated that ACMs had more hemocompatibility. Cytotoxicity tests indicated that ACMs initially had less cell attached proliferation but increased with incubation. In contrast, the relative growth rate of mouse embryo fibroblasts (MEFs) on CMs decreased gradually. The results suggested that ACMs could stimulate the growth of MEFs, and CMs were not cytotoxic to MEFs. Thus, ACMs were more biocompatible with greater potential to be used as chemoembolic material. [ABSTRACT FROM AUTHOR]

Drug delivery mediated by hydrogel has shown great promise in controlled drug release field. We report here the development of a hydroxybutyl chitosan (HBC) thermo-sensitive gel to deliver doxorubicine hydrochloride (DOX·HCl) for cancer treatment. Concentrated HBC aqueous solution could transform into hydrogel within 30 s after injection under physiological temperature in non-chemical fashion. The properties of the HBC gels including chemical structure, surface morphology, and rheologic properties were studied. Gelation temperature and gelation time of HBC could be adjusted by HBC concentrations. The gel erosion rate in vivo was faster than solubilization rate in vitro. The mild inflammatory response caused by implantation of the hydrogel was acceptable. The DOX·HCl (1 mg/ml) loaded HBC gels displayed slow release rates that were independent of the HBC concentration, and significantly reduced viability of 4T-1 cells compared with the HBC gels after 1 day incubation. These results indicate that thermo-sensitive HBC hydrogels have promising potential as an injectable drug carrier for pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Abstract: To develop a functional nanosized transdermal drug delivery system for tumor therapy, amphiphilic hyaluronic acid (HA) based niosome was constructed combining transdermal and tumor targeting ability in one entity. HA esterified with monostearin, the conjugate labeled as HA–GMS self-assembled onto niosome surface and formed HA–niosome. The multilayer vesicle had small size (around 40nm), good stability and desirable drug encapsulating efficacy, and well compatible with blood. It exhibited better endocytosis to mouse breast tumor cell (4T1) than the control chitosan nanoparticle, which was verified qualitatively and quantitatively. Skin permeation of HA–niosome was proven to be efficient using in vitro stratum corneum model and in vivo fluorescence observation. Histological section study confirmed the security and efficiency of transdermal permeation. The results evidence HA–niosome to be exciting and promising for tumor therapy through trandermal administration. [Copyright &y& Elsevier]

Abstract: The present work described nanoparticles (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) using coacervation process as novel potential carriers for gene delivery. An N/P ratio of 5 and OCMCS/HA weight ratio of 4 were the optimal conditions leading to the smallest (164.94nm), positive charged (+14.2mV) and monodispersed NPs. OCMCS-HA/DNA (OHD) NPs showed higher in vitro DNA release rates and increased cellular uptake by Caco-2 cells due to the HA involved in NPs. The MTT survival assay indicated no significant cytotoxicity. The transfection efficiency of OHD NPs was 5-fold higher than OCMCS/DNA (OD) NPs; however, it decreased significantly in the presence of excess free HA. The results indicated that OHD NPs internalized in Caco-2 cells were mediated by the hyaluronan receptor CD44. The data obtained in the present research gave evidence of the potential of OHD NPs for the targeting and further transfer of genes to the epithelial cells. [Copyright &y& Elsevier]

Abstract: Oleoyl-carboxymethyl-chitosan (OCMCS) was synthesized and were soluble at neutral pH. The critical micelle concentration (CMC) of OCMCS in deionized water was 0.021mg/ml. OCMCS nanoparticles were successfully prepared via self-assembly with mean diameter of 215.34nm, zeta potential of 19.26mV and an almost spherical shape as determined by electron microscopy. The OCMCS nanoparticles showed low erythrocyte membrane-damaging effect. The MTT survival assay indicated no significant cytotoxicity to Caco-2 cells and MEFs cells. The uptake of FITC labeled OCMCS nanoparticles by Caco-2 cells was confirmed via confocal laser scanning microscope (CLSM). In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of carps. The extent of tissue distribution and retention following oral administration of FITC-OCMCS nanoparticles was analyzed for 3 days. After 3 days, the nanoparticles remained detectable in the muscle, heart, kidney, liver, intestine, and spleen. The results showed that 34.32% of the particles were localized in the liver, 18.79% in the kidney, and 17.36% in the heart. The lowest percentage was observed in the muscle. These results implied that OCMCS nanoparticles had great potential to be applied as safe carriers for the oral administration of protein drugs. [Copyright &y& Elsevier]

Abstract: Chemical modification of chitosan by grafting with PLA (CS-g-PLA) was developed via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) mediated coupling reaction. The introduction of PLA disrupted the crystalline structure of chitosan, improved its solubility and thermal stability. Low degree of PLA substitution showed better degradation efficiency than chitosan and PLA. Weight loss of CS-g-PLA6 and CS-g-PLA4 was 87% and 94%, respectively, in 7 days enzymatic degradation study. CS-g-PLA2 was totally degraded in 1 day. Self-assembly behavior was studied using pyrene fluorescence dye technique and found to be PLA grafting level dependent. CS-g-PLA with low grafting degree showed hydrophilic, self-assembling properties and controllable biodegradability that may widen its applications. [Copyright &y& Elsevier]

Abstract: Owing to its high biodegradability, and nontoxicity and antimicrobial properties, chitosan is widely-used as an antimicrobial agent either alone or blended with other natural polymers. To broaden chitosan''s antimicrobial applicability, comprehensive knowledge of its activity is necessary. The paper reviews the current trend of investigation on antimicrobial activities of chitosan and its mode of action. Chitosan-mediated inhibition is affected by several factors can be classified into four types as intrinsic, environmental, microorganism and physical state, according to their respective roles. In this review, different physical states are comparatively discussed. Mode of antimicrobial action is discussed in parts of the active compound (chitosan) and the target (microorganisms) collectively and independently in same complex. Finally, the general antimicrobial applications of chitosan and perspectives about future studies in this field are considered. [Copyright &y& Elsevier]

Abstract: In this study, we investigated the antibacterial mechanism through the interfacial contacting inhibition behaviors of chitosan antimicrobials against Escherichia coli in solid dispersing state. Chitosan microspheres (CMs) were prepared by emulsification cross-linking reaction, and oleoyl-CMs (OCMs) were obtained by introduction of oleoyl groups to the chitosan. The CMs were with smooth surface and spherical shape of diameter of about 124μm. The antibacterial activity was directly proportional to the concentration and the hydrophobic property of CMs. The fluorescence experiments indicated CMs had influenced the structure of membrane, especially the OCMs were speculated to interact with proteins on the cell membrane. SEM photographs showed E. coli adhered to the surface of the CMs and provided evidences for the disruption of the cells, while the bacterium conglomerated on the surface of the OCMs. The CMs changed the permeability of membrane and caused cellular leakage that correlated with the hydrophobic interaction between CMs and cytoplasmic membrane phospholipids of Gram-negative bacteria. Solid dispersing system makes the antibacterial activities of CMs counted as a sequent event-driven to study the antibacterial mechanism of chitosan originally. [Copyright &y& Elsevier]

• HBC was prepared using KOH/urea dissolution system. • HBC self-assembled into nanoparticles between 4−37 °C. • HBC nanoparticles exhibit superior flocculation capacity of anions. • Excellent antibacterial, hemostatic, antioxidant and water treatment capabilities. • HBC nanoparticles could be applied in biomedicine and water treatment. Hydroxybutyl chitosan (HBC) with different degree of substitution (DS) were prepared using a homogeneous reaction system (KOH/urea), which could achieve temperature-dependent reversible morphological transition in aqueous solution. During hydrophobic assembly, amino groups on HBC chains exposed on the surface of nanoparticles formed a poly-cationic structure. The structure of HBCs was characterized by FTIR, 13C NMR, XRD, TGA and rheology. The morphology and assembly mechanism of HBC nanoparticles were studied by TEM, AFM and DLS. Also, the results of coagulation, bacteriostatic, superoxide anion clearance and anionic contaminant removal tests suggested that HBC nanoparticles had excellent flocculation and removal effect of anionic composites. Moreover, the cytocompatibility test indicated that HBC could effectively promote proliferation and division of mouse fibroblast, mouse embryonic fibroblast and rat bone marrow mesenchymal stem cells. These cationic HBC nanoparticles exhibited great potential in multi-functional applications. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a novel surface fluid-swellable chitosan (SFSC) fiber for potential wound dressing. The SFSC fiber was successfully prepared by surface modification of chitosan fiber with succinic anhydride, which was characterized by FTIR and solid-state 13 C NMR. The SFSC fiber exhibited better water absorption capacity (approx. 2980%) and stronger antibacterial activities (both above 90%) against Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) than chitosan fiber (both below 75%). The cell viability was more than 90% after treated with the SFSC fiber extract, which demonstrated that SFSC fiber had low cytotoxicity towards mouse embryo fibroblasts (MEFs). The SFSC fiber could promote wound healing with advanced development of granulation tissue and epithelial coverage compared with the control (gauze-covered) group. The results indicated that SFSC fiber had great potential to be used as wound dressing material. [ABSTRACT FROM AUTHOR]

To develop more effective anticancer mucoadhesive drug delivery system for the treatment of colorectal cancer, chitosan based nanogels (NGs) were prepared by electrostatic interaction between chitosan (CS) and carboxymethyl-chitosan (CMCS). By respectively using tripolyphosphate (TPP) and CaCl 2 as ionic crosslinker, two well-characterized doxorubicin hydrochloride (DOX) loaded NGs with opposite zeta potential (DOX:CS/CMCS/TPP NGs, −32.6 ± 1.1 mV and DOX:CS/CMCS/Ca 2+ NGs, +31.8 ± 0.9 mV) were obtained. Compared with DOX:CS/CMCS/TPP NGs, DOX:CS/CMCS/Ca 2+ NGs were taken up to a greater extent by colorectal cancer cells, resulting in greater reduction in percentage of cell viability. Owing to high binding capability to mucin and inhibited paracellular transport by colon, DOX:CS/CMCS/Ca 2+ NGs exhibited improved mucoadhesion and limited permeability. This is beneficial to prolong the contact time of formulation onto intestinal mucosa and improved local drug concentration. The results provided evidence DOX:CS/CMCS/Ca 2+ NGs to be exciting and promising for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract: Two types of poly-lactic-co-glycolic acid (PLGA) based nanoparticles were prepared by surface modification (C-NPs) and homogeneous modification (G-NPs) with chitosan. The naked PLGA NPs were served as control. These nanoparticles all showed regularly spherical shape with mean diameters as 191.3±3.6nm, 211.9±13.2nm and 187.5±17.6nm for PLGA NPs, C-NPs and G-NPs, respectively. Their zeta potentials were −22.4±1.31mV, −8.7±0.45mV, −3.1±0.12mV, respectively. Both C-NPs (15.3% PLGA remained after 2 weeks) and G-NPs (3.7% PLGA remained after 2 weeks) had higher hydrolysis rate than PLGA NPs (18.4% PLGA remained after 6 weeks), with G-NPs showing the highest rate in hydrolysis due to the incorporation of chitosan and its self-assembled structure. Self-assembling properties and controllable biodegradability of G-NPs indicated that it could be a promising drug delivery carrier for tumor drug delivery. [Copyright &y& Elsevier]

In situ 3D printing technologies is a new frontier for highly personalized medicine, which requires suitable bioink with rheology, biocompatibility, and gelation kinetics to support the right shape and mechanical properties of the printed construct. To this end, a facile design of thermo/photo dual cure composite hydrogel was proposed using MHBC and soluble collagen in this study. M/C composite hydrogel exhibited rapid thermo-induced sol-gel transition and contraction, tunable mechanical properties, proper microstructure and biodegradability for 3D cell culture, as well as improve cyto-compatibility, all of which were dependent upon the methacrylation degree of MHBC and M/C ratios. The printability of the optimal formulation (3% MHBC/1% collagen) was validated by its mild printing condition, rapid gelation of bioink at 37 °C and simple postprocessing manipulation. Both desirable printability and cyto-compatibility enable M/C composite hydrogel a potential candidate as bioink to be applied for in situ 3D bioprinting. • The composite hydrogel was prepared by thermo/photo dual cure. • The composite hydrogel formed rapidly under room temperature by sol-gel transition. • The composite hydrogel provided RGD motif to significantly enhance cell adhesion. • The composite hydrogel exhibited desirable printability and biocompatibility. • The composite hydrogel could be a potential bioink for in situ 3D bioprinting. [ABSTRACT FROM AUTHOR]

Abstract: Oleoyl-carboxymethy-chitosan (OCMCS) nanoparticles based on chitosan with various molecular weights were prepared using coacervation process, which demonstrated particle size of 150–350nm, zeta potential of 10–20mV, and high encapsulation efficiency of fluorescein isothiocyanate dextran (FD4). OCMCS nanoparticles were found to be adsorbed onto the excised carp intestinal mucosa, the extent of adsorption increased with increasing chitosan molecular weight. In comparison to FD4 solution, OCMCS nanoparticles promoted FD4 transport through excised carp intestinal mucosa by 3.26–6.52 folds, which were observed via fluorescence microscope. The OCMCS nanoparticulate systems that interacted with the Caco-2 cells decreased the transepithelial electric resistance (TEER) and induced increasing the apparent permeability coefficient (P app) of FD4 by 3.61–6.32 folds. Cytotoxicity studies in Caco-2 monolayers verified the safety of the delivery system. The improvement of mucoadhesive ability and permeability enable the OCMCS nanosystems suitable carriers for the intestinal absorption of protein drugs. [Copyright &y& Elsevier]

Abstract: A novel chitosan antibacterial dispersion system was prepared by oleoyl-chitosan (O-chitosan) nanoparticles (OCNP) and the bactericidal activity against Escherichia coli and Staphylococcus aureus was evaluated by the enumeration of viable organisms at different incubation times. We further investigated the antimicrobial mode of OCNP using a combination of approaches, including cell integrity measurements, outer membrane (OM) and inner membrane (IM) permeabilization assays, SDS–PAGE and transmission electron microscopy (TEM). Results showed that when treated with OCNP, release of intracellular components quickly increased for both E. coli and S. aureus. OCNP also rapidly increased the 1-N-phenylnaphthylamine (NPN) uptake and the release of cytoplasmic β-galactosidase via increasing the permeability of OM and IM. Besides, SDS–PAGE indicated the content of cellular soluble proteins decreased significantly in OCNP-treated bacteria. TEM observations demonstrated adsorption behaviors of OCNP on bacteria and extensive cell surface alterations of OCNP-treated bacteria. OCNP has potential value in the determination of antibacterial mechanism of chitosan. [Copyright &y& Elsevier]

Abstract: A thermosensitive hydrogel has been prepared with chitosan and αβ-glycerophosphate (αβ-GP) which could be transited from solution into gel at 37°C. The thermosensitive characteristics, appearance and structure of the hydrogel were affected by concentration, molecular weight and degree of deacetylation (DD) of chitosan. Chitosan, MW 1360kDa, DD 75.4%, solution concentration 2% was optimal for preparation of chitosan-αβ-glycerophosphate (CS-αβ-GP) thermosensitive hydrogel. The appearance of the hydrogel became more compact and regular with increasing concentration and chitosan MW. Model drugs release from CS-αβ-GP hydrogel prepared by the drug being added into chitosan solution (method I) was slower than that from hydrogel prepared by the drug being directly added into chitosan hydrogel (method II).The release rate for both adriamycin and 6-mercaptopurine from CS-αβ-GP hydrogel decreased with the increase of MW of the chitosan. The hydrophilic model adriamycin was released 60–70% over 24h which was slower than that of the hydrophobic model 6-mercaptopurine. Therefore it was projected that the CS-αβ-GP hydrogel should be an ideal sustained release system especially for hydrophilic drugs. [Copyright &y& Elsevier]

Highlights • Quercetin-chitosan micelle was used as an oral delivery of doxorubicin. • The drug loaded micelles could maintain stability and slowly release of drug. • The micelles could promot the doxorubicin absorption by permeation enhancement. Abstract In this study, quercetin-chitosan conjugate (QT-CS) was synthesized for oral delivery of doxorubicin (DOX) to improve its oral bioavailability by increasing its water solubility, opening tight junction and bypassing the P-glycoprotein (P-gp). The prepared QT-CS self-assembled into micelles which could encapsulate DOX with high encapsulation rate, small particle size (136.9 nm) and strong zeta potential (+16.2 mV). QT-CS-DOX micelles displayed sustained-release profile in gastrointestinal simulation fluid (pH 1.2/pH 7.4). QT-CS micelles could promote cellular uptake of doxorubicin, which was 2.2 folds higher than that of free doxorubicin. The trans epithelial electrical resistance (TEER) value of Caco-2 monolayer cells was significantly reduced (about 57%) by drug loaded QT-CS micelles, leading to a high apparent permeability coefficient (P app) of doxorubicin, which was 10.17 folds higher than that of free doxorubicin. Above results indicate that QT-CS micelles are promising vehicles for the oral delivery of insoluble anticancer drugs. [ABSTRACT FROM AUTHOR]

Abstract The novel solvent (0.25 M KOH/0.01 M urea alkaline solution) was used to successfully dissolve chitosan without freezing-thawing cycles, for the first time. The results from XRD, FTIR, and 13CNRM proved that KOH/urea solution could destroy the hydrogen bonds between chitosan chains more efficiently than NaOH/urea solution. The dynamic light scattering, rheology, viscosity and elemental analysis confirmed that the KOH/urea hydrogen-bonded chitosan complex had a better thermal stability at 40 °C, and no obvious deacetylation and degradation appeared in dissolution process. Subsequently, the homogeneous chemical modification of chitosan based on KOH/urea dissolution system solution was conducted at 25 °C. The FTIR and microscopic observation indicated that the carboxymethyl chitosan, N , N , N -trimethyl chitosan and hydroxyl butyl chitosan were synthetized successfully. This work provided a green and stable solvent for homogeneous chemical modification of chitosan. Graphical abstract Unlabelled Image Highlights • A green and stable method to dissolve chitosan in KOH/urea • The chitosan alkaline solution showed good thermal stability. • The homogeneous modification of chitosan was conducted in this alkaline system successfully. [ABSTRACT FROM AUTHOR]

This work targeted to investigate the potential of thermo-responsive hydroxybutyl chitosan (HBC) hydrogel using as an embolic material for occlusion of selective blood vessels. HBC hydrogel was prepared via an etherification reaction between chitosan (CS) and 1, 2-butene oxide. The hydroxybutyl groups were introduced into CS backbone, which endowed HBC hydrogel with properties of porous structure, favorable hydrophilia and rapid sol-gel interconvertibility. The gelation temperatures and gelation time respectively decreased from 30.7 °C to 11.5 °C and 79.60 ± 3.19 s to 7.70 ± 1.42 s at 37 °C, with HBC solutions viscoelasticity increased from 3.0% to 7.0%. HBC hydrogel exhibited noncytotoxic to mouse embryo fibroblasts (MEFs) and excellent hemocompatibility with red blood cells (RBCs). After injection HBC solution into rat renal arteries, HBC solution transformed into hydrogel and attached onto blood vessel inner wall tightly, giving immediate blood vessels embolization. Meanwhile, RBCs could aggregate around HBC hydrogel to form moderate coagulation, which was beneficial to avoid hydrogel migration with blood flow. Above results suggested that HBC hydrogel could be applied as a promising embolic agent for hemorrage in the interventional vascular embolization field. [ABSTRACT FROM AUTHOR]

The primary constraints for efficient oral delivery of anticancer drugs include the efflux pump function of the multidrug transporter P-glycoprotein (P-gp) for anticancer drugs and the barriers to drug absorption in gastrointestinal (GI) tract. To improve bypassing P-gp drug efflux pumps and oral bioavailability of doxorubicin hydrochloride (DOX), Multilayer micro-dispersing system (MMS) was constructed by co-immobilization of DOX loaded chitosan/carboxymethyl chitosan nanogels (DOX:CS/CMCS-NGs), along with quercetin (Qu) in the core of multilayer sodium alginate beads (DOX:NGs/Qu-M-ALG-Beads). The obtained DOX:NGs/Qu-M-ALG-Beads possessed layer-by-layer structure and porous core with many nanoscale particles. The swelling characteristic and drug release results indicated that DOX:NGs/Qu-M-ALG-Beads exhibited favorable gastric acid tolerance and targeting release of intact DOX:CS/CMCS-NGs and Qu in small intestine. After oral administration of DOX:NGs/Qu-M-ALG-Beads in rats, DOX was effectively delivered into systemic circulation due to P-gp inhibitory properties of Qu. The absolute bioavailability reached 55.75%, about 18.65 folds higher than oral DOX. Tissue distribution results showed that the liver exhibited the highest DOX level, followed by kidney, heart, lung, and spleen. These results implied that DOX:NGs/Qu-M-ALG-Beads had great potential to be applied as dual drug delivery for oral chemotherapy. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the efficacy of nanoparticles based on chitosan as a vehicle for oral antigen delivery in fish vaccination. Carboxymethyl chitosan/chitosan nanoparticles (CMCS/CS-NPs) loaded extracellular products (ECPs) of Vibrio anguillarum were successfully developed by ionic gelation method. The prepared ECPs-loaded CMCS/CS-NPs were characterized for various parameters including morphology, particle size (312 ± 7.18 nm), zeta potential (+17.4 ± 0.38 mV), loading efficiency (57.8 ± 2.54%) and stability under the simulated gastrointestinal (GI) tract conditions in turbot. The in vitro profile showed that the cumulative release of ECPs from nanoparticles was higher in pH 7.4 (58%) than in pH 2.0 (37%) and pH 4.5 (29%) after 48 h. Fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) was used as model protein antigen and encapsulated in CMCS/CS-NPs for investigating the biodistribution of antigen after oral delivery to turbot in 24 h. Oral immunization of ECPs-loaded CMCS/CS-NPs group in turbot showed elevated specific antibody and higher concentrations of lysozyme activity and complement activity in fish serum than ECPs solution. CMCS/CS-NPs loaded with ECPs could enhance both adaptive and innate immune responses than the group treated with ECPs solution and suggested to be a potential antigen delivery system. [ABSTRACT FROM AUTHOR]

Here we described nano-polyplexes (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) as novel potential carriers for oral gene vaccines delivery. Aerolysin gene (aerA) of Aeromonas hydrophila as microbial antigen was efficiently loaded to form OCMCS-HA/aerA (OHA) NPs. OHA NPs performed the optimal parameters, i.e. smallest (154.5 ± 9.4 nm), positive charged (+7.9 ± 0.5 mV) and monodispersed system with the N/P ratio of 5 and OCMCS/HA weight ratio of 4. Upon the introduction of HA, OHA NPs was beneficial for the DNA release in intestinal environments in comparison to OA NPs. The mean fluorescence intensity detected in Caco-2 cells incubated with OHA NPs was about 2.5-fold higher than that of OA NPs; however, it decreased significantly in the presence of excess free HA. The OHA NPs and OA NPs decreased the transepithelial electric resistance (TEER) of Caco-2 monolayers obviously and induced increasing the apparent permeability coefficient ( P app ) of DNA by 5.45–6.09 folds compared with free DNA. Significantly higher (P < 0.05) antigen-specific antibodies were detected in serum after orally immunized with OHA NPs than that immunized with OA NPs and DNA alone in carps. These results enable the OHA NPs might resolve challenges arising from gastrointestinal damage to gene antigens, and offer an approach applicable for oral vaccination. [ABSTRACT FROM AUTHOR]

In the present work, N,N,N -trimethyl chitosan (TMC) fibers were synthesized successfully and the resulting quaternized materials were characterized by FTIR. The designed TMC fibers with different degree of quaternization achieved high water absorption capability. In antibacterial activity study, TMC fibers showed high antibacterial activity than chitosan fibers against the gram-negative bacteria Escherichia coli (>63%) and gram-positive bacteria Staphylococcus aureus (>99%). TMC fibers exhibited no obvious cytotoxicity to mouse embryo fibroblast cells with low extraction concentrations (<0.05 g/mL). In animal wound healing test, TMC2 fibers could significantly enhance wound re-epithelialization and contraction compared with the control (chitosan fibers). In conclusion, TMC fibers have a potential to be used as wound dressing materials. [ABSTRACT FROM AUTHOR]

To develop efficient and safe anticancer drug doxorubicin hydrochloride (DOX) delivery system for oral chemotherapy, chitosan based nanoparticles (CS/CMCS–NPs) composed of chitosan (CS) and o-carboxymeymethy chitosan (CMCS) were immobilized in multilayer sodium alginate beads (NPs–M–Beads). Two kinds of NPs–M–Beads, with or without porous core, were respectively prepared by internal or external ionic gelation method. In the small intestine, the intact CS/CMCS–NPs were able to escape from porous-beads and sustained release the loading DOX. In vivo results showed that the DOX could be efficiently absorbed by small intestine of SD rat and the higher concentration of the DOX in major organs of rats were found after oral administration of Porous-Beads, which were about 2–4 folds higher than that of non-porous-beads. These results suggested that the NPs–M–Beads with porous core to be exciting and promising for oral delivery of DOX. [ABSTRACT FROM AUTHOR]

To develop insulin delivery system for the treatment of diabetes, two insulin-loaded nanogels with opposite zeta potential (−15.94 ± 0.449 mV for insulin:CMCS/CS-NGs(−) and +17.15 ± 0.492 mV for insulin:CMCS/CS-NGs(+)) were obtained. Ex vivo results showed that the nanogels with opposite surface charge exhibited different adhesion and permeation in specific intestinal segments. There was no significant differences in adhesion and permeation in rat duodenum, but in rat jejunum, insulin:CMCS/CS-NGs(−) exhibited enhanced adhesion and permeation, which were about 3 folds (adhesion) and 1.7 folds (permeation) higher than insulin:CMCS/CS-NGs(+). These results demonstrated that the surface charge property of nanogels determined the absorption sites of CMCS/CS-NGs in small intestine. In vivo study, the blood glucose level in insulin:CMCS/CS-NGs(−) group had 3 mmol/L lower than insulin:CMCS/CS-NGs(+) group during 1 h to 11 h after the oral administration, which demonstrated that negative insulin:CMCS/CS-NGs had a better management of blood glucose than positive ones. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is characterized by low pH, hypoxia, and infiltrated tumor-associated macrophages (TAMs). Therefore, regulation of TAMs polarization into anti-tumor M1 phenotype and meanwhile alleviation of the hypoxia in TME are expected to improve anti-tumor therapeutic efficacy. To this end, a novel in situ injectable nano-complexed hydrogel was developed in this study for combining tumor therapy. Thereunto, hyaluronic acid modified transfersomes loaded with chlorogenic acid functioned to reverse M2 type into M1 type via CD44 mediated internalization, the nanomedicine was entrapped in Schiff-based crosslinked injectable hydrogel (fabricated with carboxymethyl chitosan and oxidized dextran) whose linkage was labile to the acidic TME for controlled drug release. Moreover, catalase was integrated in the hydrogel enabling to convert hydrogen peroxide in TME into dissolved oxygen and alleviate tumor hypoxia. The multifunctional nano-complexed injectable hydrogel was verified to efficiently inhibit tumor growth through synergetic effects of hypoxia alleviation and TAMs polarity regulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Chitosan/carboxymethyl chitosan nanogels (CS/CMCS-NGs) could enhance the oral bioavailability of doxorubicin hydrochloride (DOX). To identify the mechanisms that support this recent observation, different transport pathways of CS/CMCS-NGs through the small intestine were studied in this work. Transcellular mechanisms were investigated in the presence of different inhibitors of protein-mediated endocytosis. A reduction of 52.32±18% of drug transport was found when clathrin-mediated endocytosis was inhibited, which demonstrated that clathrin-mediated endocytosis played an important role in the transcellular transport of DOX:CS/CMCS-NGs. The paracellular transport results showed that CMCS in NGs could produce a transient and reversible enhancement of paracellular permeability by depriving Ca2+ from adherens junctions, whose efficacy as an absorption enhancer was about 1.7–3.3 folds higher than CS in NGs in GI tract. Finally, in vivo experiment showed that the transport capacity of DOX:CS/CMCS-NGs was significantly inhibited by extra added Ca2+, which confirmed that the higher capacity to binding Ca2+ of CS/CMCS-NGs was beneficial for transport of DOX. [Copyright &y& Elsevier]

Abstract: The present study investigated the ability of a polyelectrolyte complex (CS/CMCS-NPs), composed of chitosan (CS) and o-carboxymeymethy chitosan (CMCS) as a pH responsive carrier for oral delivery of doxorubicin hydrochloride (DOX). The obtained CS/CMCS-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency and stability under the simulated GI tract conditions. The pH responsive stability of the DOX-loaded CS/CMCS nanoparticles (DOX:CS/CMCS-NPs) determined the drug release rate, which was lower in acidic pH than the neutral. Ex vivo intestinal adhesion and permeation indicated DOX:CS/CMCS-NGs were able to enhance absorption of DOX throughout the entire small intestine, especially in jejunum and ileum. Oral administration of DOX:CS/CMCS-NPs was effective to deliver DOX into blood, giving an absolute bioavailability of 42%. The tissue distribution and toxicity of DOX:CS/CMCS-NPs in rats showed low level of DOX in heart and kidney, and obviously decreased cardiac and renal toxicities. These results indicated CS/CMCS-NPs were highly efficient and safe as an oral delivery system for DOX. [Copyright &y& Elsevier]

• CtNWs are incorporated with Schiff base crosslinking Chitosan/Dextran based hydrogel. • CtNWs significantly strengthen the mechanical and adhesive properties of CD hydrogel. • CtNWs complexed CD hydrogel is non-toxic, antibacterial, degradable and hemostatic. • CtNWs complexed adhesive avoids severe postoperative adhesion and necrosis. Schiff base reaction crosslinking hydrogels are advantageous by rapid formation and absence of external crosslinkers. However, poor mechanical hindered their broader applications. Here, a mechanically strengthened tissue adhesive was constructed through incorporation of chitin nano-whiskers (CtNWs) with a Schiff base crosslinking hydrogel of carboxymethyl chitosan (CMCS) and dextran dialdehyde (DDA). The optimal formulation of complexed hydrogel exhibited 1.87 folds higher compressive stress than non-complexed and 1.51 time higher adhesive strength on porcine skin. The complexed hydrogel exhibited negligible cytotoxicity, anti-swelling performance in PBS, optimum antibacterial and hemostatic capacities. In vivo implantation studies confirmed the complexed hydrogel was degradable without long-term inflammatory responses. Desirable efficacy of injectable complexed hydrogel as hemostat was demonstrated in rat liver injury model, which could avoid severe postoperative adhesion and necrosis as observed in the treatment with commercial 3 M™ vetbond™ tissue adhesive. The results highlighted that the complexed hydrogel potentiated rapid hemostasis and wound repair applications. [ABSTRACT FROM AUTHOR]

• The composite hydrogel was prepared by thermo-crosslinking and photo-crosslinking. • The composite hydrogel displayed controlled and repeatable contraction property. • The composite hydrogel provided RGD motif to significantly enhance cell adhesion. • The cell-laden composite hydrogel could be applied for contraction fabrication. Stimuli-responsive gel volume variation is reversible and has shown promising applications, which may be potential for contraction or expansion fabrication, generating shrinking or swelling volume of the original. In this study, a thermo/photo dual-crosslinking hydrogel is prepared with methacrylated hydroxylbutyl chitosan (MHBC) and gelatin methacrylate (GelMA). The M/G hydrogel undergoes sol-gel phase transition under room temperature and shrinking deformation upon elevating temperature. Besides nontoxicity and biodegradability, dual crosslink endowed the composite hydrogel with strengthened and tunable mechanical property, controlled and repeatable contraction property in response to temperature elevation from 25 ℃ to 37 ℃, and enhanced cell adhesion in 3D culture. These peculiarities of M/G hydrogel provide great potential for application in contraction fabrication to acquire high resolution or small scale features that may be limited by fabrications devices. [ABSTRACT FROM AUTHOR]