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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]

pH-responsive nanoparticles (NPs) comprised of degradable carboxymethyl chitosan (CMCS) crosslinked with CaCl 2 were simply prepared via ionic gelation. Fabrication conditions including insulin dosage, CMCS concentration, and crosslinking density were systematically investigated for insulin loading and release in vitro . The encapsulation efficiencies (EE), loading capacity (LC) and average size of the NPs decreased with the increasing insulin concentrations (<0.192 mg/mL), while they notably increased as the insulin dosage was above 0.192 mg/mL. When the concentration of CMCS increased from 0.5 to 2.0 mg/mL, the EE of the NPs reduced while the size of the NPs increased. We further demonstrated that crosslinking density offered a simple method for tuning the properties of the NPs towards various insulin concentrations. The mass ratio 10:5 of CMCS to CaCl 2 exhibited the optimal performance at higher insulin concentration, whereas a higher crosslinking density of 10:7 (m:m) gave the optimal performance at low insulin concentration. The cumulative release of insulin from insulin loaded NPs decreased with the elevating crosslinking density. These findings not only provided a better understanding of the synthesis of CMCS NPs but also contributed to the practical applications of insulin loading and release. [ABSTRACT FROM AUTHOR]

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]

Chemodynamic therapy (CDT) has been widely used in the treatment of many kinds of tumors, which can effectively induce tumor cell apoptosis by using produced reactive oxygen species (ROS). In this paper, ROS-sensitive multifunctional marine biomaterial natural polysaccharide nanoparticles were designed. Aggregation-induced emission (AIE) molecules tetraphenylethylene (TPE) labeled and caffeic acid (CA) modified fucoidan (FUC) amphiphilic carrier material (CA-FUC-TK-TPE, CFTT) was fabricated, in which the thioketal bond(TK) was used as the linkage arm between TPE and fucoidan chain, giving the CFTT material ROS sensitivity. In addition, amphiphilic carrier material (FUC-TK-VE, FTVE) composed of thioketal-linked vitamin E and fucoidan was synthesized. The mixed carrier material CFTT and FTVE self-assembled in water to form nanoparticles (CFTT – FTVE@PTX-Fe3+) loaded with PTX and Fe3+. The CDT effect was combined with the chemotherapeutic drug PTX to achieve tumor inhibition. In vitro cell studies have proved that CT/PTX nanoparticles have excellent cell permeability and tumor cytotoxicity. In vivo antitumor experiments confirmed effective antitumor activity and reduced side effects. [ABSTRACT FROM AUTHOR]

Transdermal drug delivery efficacy of hyaluronic acid dissolving microneedles (HA DMNs) is limited by low loading dose and poor drug condensation in needles. HA swelling MNs (HA SMNs) could improve the efficacy, but comparisons between the formulations is missing. In this work, DMNs and SMNs were fabricated of HA and methacrylated HA, respectively. Their properties of transdermal drug delivery were systematically compared. HA SMNs exhibited enhanced mechanical strength, fast swelling performance, and extended duration of microchannels in skin. The doxorubicin (DOX) loaded by one-step loading protocol in needles and baseplate of SMNs could be transdermally delivered through the diffusing path mediated by swollen needles, conquering the limit of poor drug condensation in DMNs needles and generated a longer Tmax but higher Cmax. The relative bioavailability of DOX/SMNs towards DOX/DMNs was 200% within 12 h. The results provide theoretical references for the application of HA MNs mediated transdermal drug delivery. • Hyaluronic acid based dissolving or swelling microneedles were fabricated. • One-step drug loading protocol was applied for preparation of DOX/MNs. • HA SMNs exhibited strengthened mechanical property and improved insertion capacity. • DOX in needles and baseplates of SMNs could be released through swollen needles. • The relative bioavailability of DOX/SMNs to DOX/DMNs was 200%. [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 Tumor-draining lymph nodes (TDLN) are major metastatic sites for many solid tumor to support tumor progression and metastasis. Lymphatic delivery is regarded as a desirable route to promote adoptive immune response via vaccination, or to achieve efficient chemotherapy for tumor metastasis. In this study, a novel dissolving microneedle was fabricated using hyaluronic acid, integrated with transfersome (T) to break the limit of transdermal cargo transit. In virtue of the insertion capacity of microneedle and the lymphatic delivering ability of transfersomes, such transfersome/microneedles complex (T/MNs) was expected to enhance lymphatic delivery. The results revealed that the microneedles were able to efficiently insert into rat skin and release the doxorubicin loaded transfersome (DOX-T) in dermis via self-dissolution. DOX-T would maintain their multilayer structure as released from dissolved microneedles. DOX-T/MN could significantly promote accumulation of DOX in lymph nodes compared to epidermal diffusion, and increased its transdermal bioavailability in plasma. The results not only are promising for chemo-therapy of tumor through lymphatic drug delivery, especially for killing the metastasized tumor cells appeared in draining lymph nodes, they also provide an efficient strategy for tumor immune-therapy using transdermal administration. Graphical abstract Unlabelled Image [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]

Multilayer alginate hydrogel beads (MAHBs), which were prepared by emulsion method, had been fabricated via the ionic crosslinking between calcium ion (Ca 2+ ) and carboxylic group of alginate and utilized as encapsulating material for oral delivery of a model probiotic bacteria Bifidobacterium breve . Optical and fluorescence microscopy obviously showed the microorganism cells were encapsulated in the core beads. The viability of B. breve cells encapsulated in MAHBs was significantly enhanced compared with ordinary free cultured ones, the top CFU per mL were (3.70 ± 0.20) × 10 7 and (2.61 ± 0.22) × 10 7 respectively. Meanwhile, B. breve cells encapsulated in MAHBs could still keep viability even after 12 h’ culture in the broth with pH value similar to gastric juice, while the free cultured cells had no activity in such culture condition. To test applicability of MAHBs for the delivery of microorganisms, a Gram-positive strain, Staphylococcus aureus , as well as a Gram-negative strain, Escherichia coli , were also employed and encapsulated in MAHBs. Similar to B. breve cells, the viability of encapsulated S. aureus cells and E. coli cells in extreme pH value environment were significantly promoted. In addition, a high α-amylase yielding efficiency Bacillus subtilis strain was found and encapsulated in MAHBs. Compared with control groups, MAHBs encapsulated B. subtilis cells produced more α-amylase after 240 h’ culture, while the release of this enzyme was sustained rather than the burst release like free cultured group, which means this system would not reduce metabolite yield while having long term sustained-release effect. In summary, MAHBs are favorable biological carrier, which has the potential of being applied to oral delivery of probiotics. [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]

Achyranthes plays the role of dredging the meridians and clearing the joints with a certain anti-inflammatory effect, peripheral analgesic activity and central analgesic activity. A novel self-assembled nanoparticles containing Celastrol (Cel) with matrix metalloproteinase (MMP)-sensitive chemotherapy-sonodynamic therapy was fabricated targeting macrophages at the inflammatory site of rheumatoid arthritis. Dextran sulfate (DS) with highly expressed SR-A receptor on the surface of macrophages is used to specifically target the site of inflammation; by introducing PVGLIG enzyme-sensitive polypeptides and ROS-responsive bonds, it can achieve the desired effect on MMP-2/9 and reactive oxygen species at the joint site. The preparation forms DS-PVGLIG-Cel&Abps-thioketal-Cur@Cel nanomicelles, referred to as D&A@Cel. The resulting micelles had an average size of 204.8 nm and the zeta potential −16.46 mV. The results show that activated macrophages can effectively capture Cel in in vivo experiments, indicating that Cel delivered by nanoparticles can significantly improve bioavailability. Fig. 1 Design and schematic illustration of Achyranthes polysaccharide based dual-responsive nano-delivery system. In the ancient classic prescription "Shentong Zhuyu Decoction", Achyranthes plays the role of dredging the meridians and clearing the joints. It can be used as a medicinal guide, guiding its medicinal power to descend to the lower part of the body to treat the "disease in the lower part". In addition, Achyranthes has a certain anti-inflammatory effect, peripheral analgesic activity and central analgesic activity. Construction of cross-linked self-assembled nanoparticles with matrix metalloproteinase (MMP)-sensitive chemotherapy-sonodynamic combination therapy targeting macrophages at the inflammatory site of rheumatoid arthritis, overcoming the low water solubility of triptolide and targeting unspecific question. [Display omitted] [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]

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]