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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

With the increasing number of oncology patients and the use of chemotherapeutic agents, tumour multidrug resistance is becoming more and more prevalent. The search for new tumour treatment strategies to overcome tumour multidrug resistance is urgent. In this study, we designed GSH and ROS dual-responsive tumour-associated macrophages (TAMs)-targeted nanoparticles (NPs) for the co-delivery of the clinical first-line anti-breast cancer chemotherapy drug paclitaxel (PTX) and baicalin (Bai), which re-educates TAMs to alter their phenotype. We synthesised oligohyaluronic acid-mannose-folic acid (oHA-Man-FA, HMF) and astragalus polysaccharide-dithiodipropionic acid-paeoniflorol (APS-S-Pae, ASP), two hybrid materials that can self-assemble in water to form hybrid nanoparticles (HP-NPs) co-loaded with paclitaxel and baicalin (HP-NPs@PTX/Bai). The experimental results show that our designed hybrid nanoparticles can be specifically released in the tumour microenvironment and deliver the antitumor drug PTX as well as Bai, which reshapes the phenotype of TAMs, to the tumour site. The hybrid nanoparticles not only effectively re-educated TAMs from M2 TAM to M1 TAM, but also ameliorated the cytotoxic side effects caused by free PTX and provided better tumour suppression than free PTX and HP.

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-Fe 3+ ) loaded with PTX and Fe 3+ . 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., (Copyright © 2022. Published by Elsevier B.V.)

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.)

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 (<0.192mg/mL), while they notably increased as the insulin dosage was above 0.192mg/mL. When the concentration of CMCS increased from 0.5 to 2.0mg/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., (Copyright © 2017. Published by Elsevier B.V.)

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.)

A series of deoxycholate-chitosan-hydroxybutyl (DAHBCs) with different degrees of substitution (DS) of hydrophobic deoxycholate (DOCA) were successfully synthesized. The lower critical solution temperature (LCST) of various DAHBCs could be adjusted from 35.4°C to 42.1°C by controlling the graft density of DOCA. DAHBCs could self-assemble into nanoparticles (NPs) which gradually evolved from irregular aggregates to spherical particles with the decrease of the DS of DOCA groups. The size of DAHBCs NPs ranged from 100nm to 250nm and their zeta potential varied between 3.85 and 12.37mV. Hemolysis tests and protein adsorption assay exhibited DAHBCs NPs had few adverse effects on the blood components even at a concentration as high as 1mg/mL. DAHBCs NPs showed high curcumin (CUR) encapsulation efficiency up to 80%. CUR-loaded DAHBCs NPs displayed thermal-dependent drug release profiles, and the release rate of CUR (∼75%) was significantly (p<0.05) accelerated at a temperature above the LCST compared with that (∼40%) below the LCST. Cytotoxicity analysis identified no toxicity associated with DAHBCs NPs at a concentration up to 0.5mg/mL. However, when the cells were incubated with the CUR-loaded NPs, their growth was significantly inhibited at 43°C (>LCST), demonstrating the thermal-responsive release of encapsulated cargoes from the NPs. With the capacity to control the LCST of DAHBCs NPs at specific temperatures, it could be speculated that DAHBCs NPs might serve as a promising thermo-responsive nanoplatform for the delivery of antitumor drugs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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±7.18nm), zeta potential (+17.4±0.38mV), 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 48h. 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 24h. 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., (Copyright © 2016. Published by Elsevier B.V.)

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±9.4nm), positive charged (+7.9±0.5mV) 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 (Papp) 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., (Copyright © 2016. Published by Elsevier B.V.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel hyaluronic acid modified transfersome was prepared to deliver drugs to lymphatics through the transdermal route. Doxorubicin loaded HA-GMS-T was able to efficiently penetrate into the deep skin tissue, leading to enhanced absorption by lymphatics. Most importantly, hyaluronic acid effectively improved the uptake of drug loaded nanocarriers by tumor cells.

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 © 2013 Elsevier B.V. All rights reserved.)

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-carboxymethyl-chitosan (OCMCS) was synthesized and were soluble at neutral pH. The critical micelle concentration (CMC) of OCMCS in deionized water was 0.021 mg/ml. OCMCS nanoparticles were successfully prepared via self-assembly with mean diameter of 215.34 nm, zeta potential of 19.26 mV 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 © 2012 Elsevier B.V. All rights reserved.)

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 ± 3.6 nm, 211.9 ± 13.2 nm and 187.5 ± 17.6 nm for PLGA NPs, C-NPs and G-NPs, respectively. Their zeta potentials were -22.4 ± 1.31 mV, -8.7 ± 0.45 mV, -3.1 ± 0.12 mV, 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 © 2012 Elsevier B.V. All rights reserved.)

Chitosan grafted poly(lactic acid) (CS-g-PLA) copolymer was synthesized and characterized by FT-IR and elemental analysis. The degree of poly(lactic acid) substitution on chitosan was 1.90 ± 0.04%. The critical aggregation concentration of CS-g-PLA in distilled water was 0.17 mg/ml. Three methods of preparing CS-g-PLA nanoparticles (diafiltration method, ultrasonication method and diafiltration combined with ultrasonication method) were investigated and their effect was compared. Of the three methods, diafiltration combined with ultrasonication method produced nanoparticles with optimal property in terms of size and morphology, with size ranging from 133 to 352 nm and zeta potential from 36 to 43 mV. Also, the hemolytic activity and cytotoxicity of the CS-g-PLA based nanoparticles was tested, and results showed low hemolysis rate (<5%) and no significant cytotoxicity effect of these nanoparticles., (Copyright © 2012 Elsevier B.V. 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]