Multimodal evaluation of blood-brain barrier opening in mice in response to low-intensity ultrasound and a claudin-5 binder.

Background: The blood-brain barrier (BBB) is a major bottleneck in delivering therapeutics to the brain. Treatment strategies to transiently open this barrier include focused ultrasound combined with intravenously injected microbubbles (FUS+MB) and targeting of molecules that regulate BBB permeability. Methods: Here, we investigated BBB opening mediated by the claudin-5 binder cCPEm (a microorganismal toxin in a truncated form) and FUS+MB at a centre frequency of 1 MHz, assessing dextran uptake, broadband emission, and endogenous immunoglobulin G (IgG) extravasation. Results: FUS+MB-induced BBB opening was detectable at a pressure ≥0.35 MPa when assessed for leakage of 10 and 70 kDa dextran, and at ≥0.2 MPa for uptake of endogenous IgG. Treating mice with 20 mg/kg cCPEm failed to open the BBB, and pre-treatment with cCPEm followed by FUS+MB at 0.2 and 0.3 MPa did not overtly increase BBB opening compared to FUS+MB alone. Using passive cavitation detection (PCD), we found that broadband emission correlated with the peak negative pressure (PNP) and dextran leakage, indicating the possibility of using broadband emission for developing a feedback controller to monitor BBB opening. Conclusions: Together, our study highlights the challenges in developing combinatorial approaches to open the BBB and presents an additional IgG-based histological detection method for BBB opening.

Membrane nanotubes transform into double-membrane sheets at condensate droplets.

Cellular membranes exhibit a multitude of highly curved morphologies such as buds, nanotubes, cisterna-like sheets defining the outlines of organelles. Here, we mimic cell compartmentation using an aqueous two-phase system of dextran and poly(ethylene glycol) encapsulated in giant vesicles. Upon osmotic deflation, the vesicle membrane forms nanotubes, which undergo surprising morphological transformations at the liquid-liquid interfaces inside the vesicles. At these interfaces, the nanotubes transform into cisterna-like double-membrane sheets (DMS) connected to the mother vesicle via short membrane necks. Using super-resolution (stimulated emission depletion) microscopy and theoretical considerations, we construct a morphology diagram predicting the tube-to-sheet transformation, which is driven by a decrease in the free energy. Nanotube knots can prohibit the tube-to-sheet transformation by blocking water influx into the tubes. Because both nanotubes and DMSs are frequently formed by cellular membranes, understanding the formation and transformation between these membrane morphologies provides insight into the origin and evolution of cellular organelles.

pH-Sensitive doxorubicin delivery using zinc oxide nanoparticles as a rectified theranostic platform: in vitro anti-proliferative, apoptotic, cell cycle arrest and in vivo radio-distribution studies.

Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide (99mTc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC50 than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 µg ml-1, respectively). The in vitro biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The in vivo experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide (99mTc), the radiolabeled platform (99mTc-labelled DOX-loaded ZnO@dextran) was in vivo monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g-1 at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, 99mTc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.

Preparation of Controlled Multicompartmental Gel Microcarriers Based on Aqueous Two-Phase Emulsions for 3D Partitioned Cell Coculture In Vitro.

A facile method was proposed for preparing controllable multicompartment gel microcarriers using an aqueous two-phase emulsion system. By leveraging the density difference between the upper polyethylene glycol solution and the lower dextran-calcium chloride (CaCl2) solution in the collection solution and the high viscosity of the lower solution, controllable fusion of core-shell droplets made by coextrusion devices was achieved at the water/water (w/w) interface to fabricate microcarriers with separated core compartments. By adjusting the sodium alginate concentration, collected solution composition, and number of fused liquid droplets, the pore size, shape, and number of compartments could be controlled. Caco-2 and HepG2 cells were encapsulated in different compartments to establish gut-liver coculture models, exhibiting higher viability and proliferation compared to monoculture models. Notably, significant differences in cytokine expression and functional proteins were observed between the coculture and monoculture models. This method provides new possibilities for preparing complex and functional three-dimensional coculture materials.

Physicochemical and Biological Properties of Vancomycin-Containing Antibacterial Polysaccharide Gels for Biocomposite Bone Implant Impregnation.

Polymeric drugs containing up to 60% by weight of the antibiotic vancomycin were synthesized based on dextran carriers activated with epichlorohydrin. Vancomycin was covalently bound, involving the primary amino group of the molecule through the hydroxypropyl radical to the C6 position of the anhydroglucose units of the dextran main chain. Covalent binding is necessary to prevent spontaneous release of the antibiotic from the gel, thereby reducing the risk of bacterial multiresistance. Antibacterial depot gels were obtained from those polymers, containing up to 17.5% by weight of polysaccharide with a cross-linking density of q = 3-5 nodes per macromolecule for the deposition of another type of drugs not covalently bound to the polymer gel. They were used to coat the surface of the internal pores of biocomposite bone implants based on bovine cancellous bone used in orthopedics. The chemical structure of the polymer was studied using 13C NMR spectroscopy and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. The stiffness of the gels was evaluated by the values of the accumulation modulus G' = 170-270 kPa and the loss modulus G″ = 3.7-4.2 kPa determined on a rheometer. Their values are close to those typical for materials used to replace soft tissue in plastic surgery. The minimum inhibitory concentration of the gels against Staphylococcus aureus P209 depends on the antibiotic content in the polymer. It equals 2.5 mg/L for vancomycin we used and 100 mg/L for a polymer containing 50% by weight of covalently bound antibiotic. The cytotoxic concentration measured with cell culture HEK 293T exceeds 1200 mg/L in 24 h exposure. The release dynamics of drugs not covalently bound to dextran from the depot gel were studied using fluorescein as a model. The release time is independent of the gel density and lasts up to 6 days for a 2 mm thick layer. Both the gel and the bone implants impregnated with it maintained consistently high antibacterial activity throughout the experiment, up to its completion after 168 h, with the local concentration of the released antibiotic at the site of bacterial attack exceeding the therapeutic level by 200 times.

Development of an injectable oxidized dextran/gelatin hydrogel capable of promoting the healing of alkali burn-associated corneal wounds.

The cornea serves as an essential shield that protects the underlying eye from external conditions, yet it remains highly vulnerable to injuries that could lead to blindness and scarring if not promptly and effectively treated. Excessive inflammatory response constitute the primary cause of pathological corneal injury. This study aimed to develop effective approaches for enabling the functional repair of corneal injuries by combining nanoparticles loaded with anti-inflammatory agents and an injectable oxidized dextran/gelatin/borax hydrogel. The injectability and self-healing properties of developed hydrogels based on borate ester bonds and dynamic Schiff base bonds were excellent, improving the retention of administered drugs on the ocular surface. In vitro cellular assays and in vivo animal studies collectively substantiated the proficiency of probucol nanoparticle-loaded hydrogels to readily suppress proinflammatory marker expression and to induce the upregulation of anti-inflammatory mediators, thereby supporting rapid repair of rat corneal tissue following alkali burn-induced injury. As such, probucol nanoparticle-loaded hydrogels represent a prospective avenue to developing long-acting and efficacious therapies for ophthalmic diseases.

Phenylboronic acid functionalized dextran loading curcumin as nano-therapeutics for promoting the bacteria-infected diabetic wound healing.

Chronic bacterial infections, excessive inflammation, and oxidative stress significantly hinder diabetic wound healing by prolonging the inflammatory phase and complicating the healing process. In this study, phenylboronic acid functionalized dextran (PODP) was developed to encapsulate curcumin, referred to as PODP@Cur. Experimental results indicate that PODP significantly improves the water solubility of curcumin and exhibits synergistic biological activity both in vitro and in vivo. PODP@Cur is capable of accelerating drug release under the pathological microenvironment with ROS accumulation. Furthermore, phenylboronic acid (PBA) has demonstrated potential for targeted bacterial drug delivery, enhancing antibacterial efficacy and trapping free LPS/PGN from dead bacteria to reduce undesirable inflammation. In a diabetic mouse model, PODP@Cur exhibits an excellent antibacterial, anti-inflammatory and antioxidant activities to ultimately promote the efficient and safe wound healing. Due to the specific interaction between PBA and LPS, PODP@Cur could enhance antibacterial activity against bacteria, reduce toxic side effects on normal cells, and alleviate the LPS-mediated pro-inflammatory pathological microenvironment. Therefore, PODP@Cur is capable of being exploited as an efficient and safe candidate for promoting the bacteria-infected diabetic wound healing.

Plasticised chitosan: Dextran polymer blend electrolyte for energy harvesting application: Tuning the ion transport and EDLC charge storage capacity through TiO2 dispersion.

This study investigates the performance of biopolymer electrolytes based on chitosan and dextran for energy storage applications. The optimization of ion transport and performance of electric double-layer capacitors EDCL using these electrolytes, incorporating different concentrations of glycerol as a plasticizer and TiO2 as nanoparticles, is explored. Impedance measurements indicate a notable reduction in charge transfer resistance with the addition of TiO2. DC conductivity estimates from AC spectra plateau regions reach up to 5.6 × 10-4 S/cm. The electric bulk resistance Rb obtained from the Nyquist plots exhibits a substantial decrease with increasing plasticizer concentration, further enhanced by the addition of the nanoparticles. Specifically, Rb decreases from ∼20 kΩ to 287 Ω when glycerol concentration increases from 10 % to 40 % and further drops to 30 Ω with the introduction of TiO2. Specific capacitance obtained from cyclic voltammetry shows a notable increase as the scan rate decreases, indicating improved efficiency and stability of ion transport. The TiO2-enriched EDCL achieves 12.3 F/g specific capacitance at 20 mV/s scan rate, with high ion conductivity and extended electrochemical stability. These results suggest the great potential of plasticizer and TiO2 with biopolymers in improving the performance of energy storage systems.

Development, characterization, and evaluation of withaferin-A and artesunate-loaded pH-responsive acetal-dextran polymeric nanoparticles for the management of malaria.

Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.

Effects of Macromolecular Cosolutes on the Kinetics of Huntingtin Aggregation Monitored by NMR Spectroscopy.

The effects of two macromolecular cosolutes, specifically the polysaccharide dextran-20 and the protein lysozyme, on the aggregation kinetics of a pathogenic huntingtin exon-1 protein (hhtex1) with a 35 polyglutamine repeat, httex1Q35, are described. A unified kinetic model that establishes a direct connection between reversible tetramerization occurring on the microsecond time scale and irreversible fibril formation on a time scale of hours/days forms the basis for quantitative analysis of httex1Q35 aggregation, monitored by measuring cross-peak intensities in a series of 2D 1H-15N NMR correlation spectra acquired during the course of aggregation. The primary effects of the two cosolutes are associated with shifts in the prenucleation tetramerization equilibrium resulting in substantial changes in concentration of "preformed" httex1Q35 tetramers. Similar effects of the two cosolutes on the tetramerization equilibrium observed for a shorter, nonaggregating huntingtin variant with a 7-glutamine repeat, httex1Q7, lend confidence to the conclusions drawn from the fits to the httex1Q35 aggregation kinetics.

The potential of a novel enzyme-based surface plasmon resonance biosensor for direct detection of dopamine.

Dopamine is one of the significant neurotransmitters and its monitoring in biological fluids is a critical issue in healthcare and modern biomedical technology. Here, we have developed a dopamine biosensor based on surface plasmon resonance (SPR). For this purpose, the carboxymethyl dextran SPR chip was used as a surface to immobilize laccase as a bioaffinity recognition element. Data analysis exhibited that the acidic pH value is the optimal condition for dopamine interaction. Calculated kinetic affinity (KD) (48,545 nM), obtained from a molecular docking study, showed strong association of dopamine with the active site of laccase. The biosensor exhibited a linearity from 0.01 to 189 µg/ml and a lower detection limit of 0.1 ng/ml (signal-to-noise ratio (S/N) = 3) that is significantly higher than the most direct dopamine detecting sensors reported so far. Experiments for specificity in the presence of compounds that can co-exist with dopamine detection such as ascorbic acid, urea and L-dopa showed no significant interference. The current dopamine biosensor with high sensitivity and specificity, represent a novel detection tool that offers a label-free, simple procedure and cost effective monitoring system.

Synthetic biodegradable microporous hydrogels for in vitro 3D culture of functional human bone cell networks.

Generating 3D bone cell networks in vitro that mimic the dynamic process during early bone formation remains challenging. Here, we report a synthetic biodegradable microporous hydrogel for efficient formation of 3D networks from human primary cells, analysis of cell-secreted extracellular matrix (ECM) and microfluidic integration. Using polymerization-induced phase separation, we demonstrate dynamic in situ formation of microporosity (5-20 µm) within matrix metalloproteinase-degradable polyethylene glycol hydrogels in the presence of living cells. Pore formation is triggered by thiol-Michael-addition crosslinking of a viscous precursor solution supplemented with hyaluronic acid and dextran. The resulting microporous architecture can be fine-tuned by adjusting the concentration and molecular weight of dextran. After encapsulation in microporous hydrogels, human mesenchymal stromal cells and osteoblasts spread rapidly and form 3D networks within 24 hours. We demonstrate that matrix degradability controls cell-matrix remodeling, osteogenic differentiation, and deposition of ECM proteins such as collagen. Finally, we report microfluidic integration and proof-of-concept osteogenic differentiation of 3D cell networks under perfusion on chip. Altogether, this work introduces a synthetic microporous hydrogel to efficiently differentiate 3D human bone cell networks, facilitating future in vitro studies on early bone development.

Proanthocyanidins-based tandem dynamic covalent cross-linking hydrogel for diabetic wound healing.

Wound healing in diabetic patients presents significant challenges in clinical wound care due to high oxidative stress, excessive inflammation, and a microenvironment prone to infection. In this study, we successfully developed a multifunctional tandem dynamic covalently cross-linked hydrogel dressing aimed at diabetic wound healing. This hydrogel was constructed using cyanoacetic acid functionalized dextran (Dex-CA), 2-formylbenzoylboric acid (2-FPBA) and natural oligomeric proanthocyanidins (OPC), catalyzed by histidine. The resulting Dex-CA/OPC/2-FPBA (DPOPC) hydrogel can be dissolved triggered by cysteine, thereby achieving "controllable and non-irritating" dressing change. Furthermore, the incorporation of OPC as a hydrogel building block endowed the hydrogel with antioxidant and anti-inflammatory properties. The cross-linked network of the DPOPC hydrogel circumvents the burst release of OPC, enhancing its biosafety. In vivo studies demonstrated that the DPOPC hydrogel significantly accelerated the wound healing process in diabetic mice compared to a commercial hydrogel, achieving an impressive wound closure rate of 98 % by day 14. The DPOPC hydrogel effectively balanced the disrupted inflammatory state during the healing process. This dynamic hydrogel based on natural polyphenols is expected to be an ideal candidate for dressings intended for chronic wounds.

Therapeutic impacts of GNE­477­loaded H2O2 stimulus­responsive dodecanoic acid­phenylborate ester­dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer­associated death in young people. GNE­477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus­responsive dodecanoic acid (DA)­phenylborate ester­dextran (DA­B­DEX) polymeric micelle delivery system for GNE­477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE­477 loaded DA­B­DEX (GNE­477@DBD) tumor­targeting drug delivery system was established and the release of GNE­477 was measured. The cellular uptake of GNE­477@DBD by three OS cell lines (MG­63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA­B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA­B­DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE­477@DBD by cells with sustained release of GNE­477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT­qPCR, demonstrated that GNE­477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE­477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2­responsive DA­B­DEX presents a promising delivery system for hydrophobic anti­tumor drugs for OS therapy.

Dextran Used in Blood Transfusion, Hematology, and Pharmaceuticals: Biosynthesis of Diverse Molecular-Specification-Dextrans in Enzyme-Catalyzed Reactions.

Dextran is an exopolysaccharide synthesized in reactions catalyzed by enzymes obtained from microbial agents of specific species and strains. Products of dextran polysaccharides with different molecular weights are suitable for diverse pharmaceutical and clinical uses. Dextran solutions have multiple characteristics, including viscosity, solubility, rheological, and thermal properties; hence, dextran has been studied for its commercial applications in several sectors. Certain bacteria can produce extracellular polysaccharide dextran of different molecular weights and configurations. Dextran products of diverse molecular weights have been used in several industries, including medicine, cosmetics, and food. This article aims to provide an overview of the reports on dextran applications in blood transfusion and clinical studies and its biosynthesis. Information has been summarized on enzyme-catalyzed reactions for dextran biosynthesis from sucrose and on the bio-transformation process of high molecular weight dextran molecules to obtain preparations of diverse molecular weights and configurations.

Cerium Dioxide-Dextran Nanocomposites in the Development of a Medical Product for Wound Healing: Physical, Chemical and Biomedical Characteristics.

PURPOSE OF THE STUDY: the creation of a dextran coating on cerium oxide crystals using different ratios of cerium and dextran to synthesize nanocomposites, and the selection of the best nanocomposite to develop a nanodrug that accelerates quality wound healing with a new type of antimicrobial effect. MATERIALS AND METHODS: Nanocomposites were synthesized using cerium nitrate and dextran polysaccharide (6000 Da) at four different initial ratios of Ce(NO3)3x6H2O to dextran (by weight)-1:0.5 (Ce0.5D); 1:1 (Ce1D); 1:2 (Ce2D); and 1:3 (Ce3D). A series of physicochemical experiments were performed to characterize the created nanocomposites: UV-spectroscopy; X-ray phase analysis; transmission electron microscopy; dynamic light scattering and IR-spectroscopy. The biomedical effects of nanocomposites were studied on human fibroblast cell culture with an evaluation of their effect on the metabolic and proliferative activity of cells using an MTT test and direct cell counting. Antimicrobial activity was studied by mass spectrometry using gas chromatography-mass spectrometry against E. coli after 24 h and 48 h of co-incubation. RESULTS: According to the physicochemical studies, nanocrystals less than 5 nm in size with diffraction peaks characteristic of cerium dioxide were identified in all synthesized nanocomposites. With increasing polysaccharide concentration, the particle size of cerium dioxide decreased, and the smallest nanoparticles (<2 nm) were in Ce2D and Ce3D composites. The results of cell experiments showed a high level of safety of dextran nanoceria, while the absence of cytotoxicity (100% cell survival rate) was established for Ce2D and C3D sols. At a nanoceria concentration of 10-2 M, the proliferative activity of fibroblasts was statistically significantly enhanced only when co-cultured with Ce2D, but decreased with Ce3D. The metabolic activity of fibroblasts after 72 h of co-cultivation with nano composites increased with increasing dextran concentration, and the highest level was registered in Ce3D; from the dextran group, differences were registered in Ce2D and Ce3D sols. As a result of the microbiological study, the best antimicrobial activity (bacteriostatic effect) was found for Ce0.5D and Ce2D, which significantly inhibited the multiplication of E. coli after 24 h by an average of 22-27%, and after 48 h, all nanocomposites suppressed the multiplication of E. coli by 58-77%, which was the most pronounced for Ce0.5D, Ce1D, and Ce2D. CONCLUSIONS: The necessary physical characteristics of nanoceria-dextran nanocomposites that provide the best wound healing biological effects were determined. Ce2D at a concentration of 10-3 M, which stimulates cell proliferation and metabolism up to 2.5 times and allows a reduction in the rate of microorganism multiplication by three to four times, was selected for subsequent nanodrug creation.

Gelatin/dextran active films incorporated with cinnamaldehyde and α-tocopherol for scallop (Patinopecten yessoensis) adductor muscle preservation.

Scallops are rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid but perishable due to their microbial growth and lipid oxidation. In this study, gelatin/dextran films containing cinnamaldehyde and α-tocopherol (0% + 0%, 0.3% + 0.3%, 0.6% + 0.6%, 0.9% + 0.9%, and 1.2% + 1.2%, w/w) as active fillers were developed by solution casting method, and their preservation effects on scallop adductor muscle refrigerated at 4°C for 0, 3, 6, 9, and 12 days were evaluated. Inclusion of the two active fillers did not influence the thermal stability of the films but created heterogenous and discontinuous film microstructure and increased the film hydrophobicity. Increase in the concentrations of active fillers lowered the mechanical properties and water vapor permeability of the films but increased their crystallinity, thickness, water contact angle, opacity, antibacterial property, and antioxidant property. The longest release times for both cinnamaldehyde and α-tocopherol were found in 95% (v/v) ethanol solution. The gelatin/dextran films containing 1.2% (w/w) of active fillers (Gelatin [Ge]/Dextran [Dx]/1.2 film) improved the chemical stability of refrigerated scallop adductor muscle. The total viable count (TVC) of the unpackaged scallop adductor muscle exceeded the recommended limit of 7 lg CFU/g on day 6 (7.07 ± 0.50 lg CFU/g), whereas the TVC of the Ge/Dx/1.2 film-packaged scallop adductor muscle was still below the limit on day 9 (5.60 ± 0.50 lg CFU/g). Thus, the Ge/Dx/1.2 film can extend the shelf life of refrigerated scallop adductor muscle by at least 3 days. Overall, the developed gelatin/dextran active packaging films are promising for the preservation of aquatic food products.

Dynamic hydrogel-metal-organic framework system promotes bone regeneration in periodontitis through controlled drug delivery.

Periodontitis is a prevalent chronic inflammatory disease, which leads to gradual degradation of alveolar bone. The challenges persist in achieving effective alveolar bone repair due to the unique bacterial microenvironment's impact on immune responses. This study explores a novel approach utilizing Metal-Organic Frameworks (MOFs) (comprising magnesium and gallic acid) for promoting bone regeneration in periodontitis, which focuses on the physiological roles of magnesium ions in bone repair and gallic acid's antioxidant and immunomodulatory properties. However, the dynamic oral environment and irregular periodontal pockets pose challenges for sustained drug delivery. A smart responsive hydrogel system, integrating Carboxymethyl Chitosan (CMCS), Dextran (DEX) and 4-formylphenylboronic acid (4-FPBA) was designed to address this problem. The injectable self-healing hydrogel forms a dual-crosslinked network, incorporating the MOF and rendering its on-demand release sensitive to reactive oxygen species (ROS) levels and pH levels of periodontitis. We seek to analyze the hydrogel's synergistic effects with MOFs in antibacterial functions, immunomodulation and promotion of bone regeneration in periodontitis. In vivo and in vitro experiment validated the system's efficacy in inhibiting inflammation-related genes and proteins expression to foster periodontal bone regeneration. This dynamic hydrogel system with MOFs, shows promise as a potential therapeutic avenue for addressing the challenges in bone regeneration in periodontitis.

Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy.

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.

Dynamic Release from Acetalated Dextran Nanoparticles for Precision Therapy of Inflammation.

Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.