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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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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, 13 C 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., (Copyright © 2020. Published by Elsevier Ltd.)

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., (Copyright © 2018. Published by Elsevier Ltd.)

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 3days 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 10mM 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 2h, respectively. While 85.2% of DOX was released within 2h as treated with 10mM GSH, suggesting the release was closely associated with structural disintegration of nanocarriers. The maximum release of DOX was obtained at 10mM GSH and pH 5.5 with 92.3% of DOX released in 5h. Confocal laser scanning microscopy observation indicated that DOX/CMCS-TCS NPs efficiently escaped from endo/lysosomes within 1h incubation with MCF-7 cells and gave the best performance in delivering DOX into nucleus in 2h. 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 0.6μg/mL following 48h 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., (Copyright © 2017. Published by Elsevier Ltd.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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 1h to 11h after the oral administration, which demonstrated that negative insulin:CMCS/CS-NGs had a better management of blood glucose than positive ones., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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 H2O2 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015. Published by Elsevier Ltd.)

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., (Copyright © 2014. Published by Elsevier Ltd.)

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 (164.94 nm), positive charged (+14.2 mV) 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 © 2012 Elsevier Ltd. All rights reserved.)

Oleoyl-carboxymethy-chitosan (OCMCS) nanoparticles based on chitosan with various molecular weights were prepared using coacervation process, which demonstrated particle size of 150-350 nm, zeta potential of 10-20 mV, 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 (Papp) 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 © 2012 Elsevier Ltd. All rights reserved.)

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: 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]

• 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]