ABSTRACT
PURPOSE: To address the issue of local drug delivery in tumor treatment, a novel nanoparticle-hydrogel superstructure, namely semi-interpenetrating polymer networks (semi-IPNs) hydrogel composed of poly (ethylene glycol) diacrylate (PEGDA) and hyaluronic acid (HA) and incorporated with paclitaxel (PTX) loaded PLGA nanoparticles (PEGDA-HA/PLGA-PTX), was prepared by in situ UV photopolymerization for the use of local drug delivery. METHODS: Using the gelation time, swelling rate and degradation rate as indicators, the optimal proportion of Irgacure 2959 initiator and the concentration of HA was screened and obtained for preparing hydrogels. Next, paclitaxel (PTX) loaded PLGA nanoparticles (PLGA-PTX NPs) were prepared by the emulsion solvent evaporation method. RESULTS: The mass ratio of the initiator was 1%, and the best concentration of HA was 5 mg/mL in PEGDA-HA hydrogel. In vitro experiments showed that PLGA-PTX NPs had similar cytotoxicity to free PTX, and the cell uptake ratio on NCI-H460 cells was up to 96% by laser confocal microscopy and flow cytometry. The drug release of the PEGDA-HA/PLGA-PTX hydrogel local drug delivery system could last for 13 days. In vivo experiments proved that PEGDAHA/PLGA-PTX hydrogel could effectively inhibit the tumor growth without causing toxic effects in mice. CONCLUSIONS: This study demonstrated that the PEGDA-HA/PLGA-PTX hydrogel is a promising local drug delivery system in future clinical applications for tumor therapy. A photopolymerized semi-interpenetrating polymer networks-based hydrogel incorporated with paclitaxel-loaded nanoparticles was fabricated by in situ UV photopolymerization, providing a promised nanoplatform for local chemotherapy of tumors.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Drug Carriers/chemistry , Hydrogels/chemistry , Neoplasms/drug therapy , Paclitaxel/administration & dosage , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Cell Line, Tumor , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Drug Compounding/methods , Drug Liberation , Humans , Hyaluronic Acid/chemistry , Mice , Nanoparticles/chemistry , Neoplasms/pathology , Polyethylene Glycols/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Xenograft Model Antitumor AssaysABSTRACT
A novel zwitterionic polymer ionic liquid functionalized magnetic nanospheres, shortly as Fe3O4@PCL-PILs, is synthesized by grafting ionic liquid VimCOOHBr onto polymer ε-caprolactone (PCL) modified magnetic nanospheres via esterification and surface-initiated free radical polymerization. This established synthesis strategy offers the obtained magnetic nanospheres with well-defined core-corona structure, compact grafting layer, favorable zwitterionic and negative-charged surface, and high magnetic susceptibility. The as-prepared Fe3O4@PCL-PILs nanospheres exhibit typical "zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC)" behaviors toward protein binding, and selectively adsorption of glycoprotein is achieved. The adsorption capacity of the magnetic nanospheres toward Immunoglobulin G is high up to 1136.4 mg g-1, and the captured Immunoglobulin G could be efficiently recovered by using 0.5% NH3 H2O (v/v) as stripping reagent, providing a recovery of 80.5%. Fe3O4@PCL-PILs nanospheres are then employed as sorbent for the selective isolation of Immunoglobulin G from human whole blood, obtaining high-purity Immunoglobulin G as demonstrated by polyacrylamide gel electrophoresis assays.
Subject(s)
Ferrosoferric Oxide/chemistry , Glycoproteins/isolation & purification , Ionic Liquids/chemistry , Magnetite Nanoparticles/chemistry , Nanospheres/chemistry , Polyesters/chemistry , Adsorption , Chromatography, Liquid/methods , Electrophoresis, Polyacrylamide Gel , Esterification , Glycoproteins/chemistry , Humans , Immunoglobulin G/blood , Immunoglobulin G/isolation & purification , Immunoglobulin G/metabolism , Microscopy, Electron, Transmission , Spectrometry, X-Ray Emission , X-Ray DiffractionABSTRACT
The application of nano drug delivery systems (NDDSs) may enhance the effectiveness of chemotherapeutic drugs in vivo. However, the short blood circulation time and poor drug release profile in vivo are still two problems with them. Herein, by using red blood cell membrane (RBCm) wrapping and pH sensitive technology, we prepared RBCm wrapped pH sensitive poly(l-γ-glutamylcarbocistein)-paclitaxel (PGSC-PTX) nanoparticles (PGSC-PTX@RBCm NPs), to prolong the circulation time in blood and release PTX timely and adequately in acidic tumor environment. The PGSC-PTX NPs and PGSC-PTX@RBCm NPs showed spherical morphology with average sizes about 50 and 100 nm, respectively. The cytotoxicity of PGSC-PTX@RBCm NPs was considerably decreased compared with that of PGSC-PTX NPs. PTX release from PGSC-PTX and PGSC-PTX@RBCm NPs at pH 6.5 was remarkably higher than those at pH 7.4, respectively. The PGSC-PTX@RBCm NPs exhibited remarkably decreased uptake by macrophages than PGSC-PTX NPs. The area under the curve within 72 h (AUC0-72h) for is significantly higher than PGSC-PTX NPs. The PGSC-PTX@RBCm NPs also showed significantly stronger growth-inhibiting effect on tumor than PGSC-PTX NPs. These results indicated that PGSC-PTX@RBCm NPs have acidic drug release sensitivity, the characteristics of long circulation, and remarkable tumor growth inhibiting effect. This study may provide an effective strategy for improving the antitumor effect of NDDS.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Drug Carriers/chemistry , Erythrocyte Membrane/metabolism , Lung Neoplasms/pathology , Nanoparticles/chemistry , Paclitaxel/analogs & derivatives , Polyglutamic Acid/analogs & derivatives , Polymers/chemistry , Biological Transport , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Drug Carriers/metabolism , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Liberation , Half-Life , Hemolysis/drug effects , Humans , Hydrogen-Ion Concentration , Lung Neoplasms/drug therapy , Paclitaxel/chemistry , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Particle Size , Polyglutamic Acid/chemistryABSTRACT
Two strains (pika_113T and pika_114) of a previously undescribed Actinomyces-like bacterium were recovered from the intestinal contents of plateau pika (Ochotona curzoniae) on the Tibet-Qinghai Plateau, China. Results from biochemical characterization indicated that the two strains were phenotypically homogeneous and distinct from other previously described species of the genus Actinomyces. Based on the comparison of 16S rRNA gene sequences and genome analysis, the bacteria were determined to be a hitherto unknown subline within the genus Actinomyces, being most closely related to type strains of Actinomyces denticolens and Actinomyces timonensis with a respective 97.2 and 97.1â% similarity in their 16S rRNA gene sequences. Phylogenetic analyses confirmed that pika_113T was well separated from any other recognized species of the genus Actinomyces and within the cluster with A. denticolens and A. timonensis. The genome of strain pika_113T displayed less than 42â% relatedness in DNA-DNA hybridization with all the available genomes of existing species of the genus Actinomyces in the NCBI database. Collectively, based on the phenotypic characteristics and phylogenetic analyses results, we propose the novel isolates as representatives of Actinomyces gaoshouyii sp. nov. The type strain of Actinomyces gaoshouyii is pika_113T (=CGMCC 4.7372T=DSM 104049T), with a genomic DNA G+C content of 71 mol%.
Subject(s)
Actinomyces/classification , Intestines/microbiology , Lagomorpha/microbiology , Phylogeny , Actinomyces/genetics , Actinomyces/isolation & purification , Animals , Bacterial Typing Techniques , DNA, Bacterial/genetics , Nucleic Acid Hybridization , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , TibetABSTRACT
BACKGROUND AND AIM: This study is aimed at investigating the tissue reactions of heterogenic and allogeneic acellular dermal matrix (ADM) mesh implanted in the vesicovaginal space in a rabbit model. METHODS: Twenty eight rabbits were implanted with heterogenic or allogeneic mesh, respectively, in the vesicovaginal space, and 4 served as the no-implantation control group. Rabbits were sacrificed at 7, 30, and 90 days after implantation. Histopathological study and immunohistochemical examination for collagen were performed. RESULTS: Heterogenic but not allogeneic mesh was identifiable at 90 days. In the allogeneic group, neovascularization was observed from day 7 after implantation. A chronic inflammatory reaction was noted in the heterogenic group at 30 days that decreased at 90 days. Inflammation was less in the allogeneic group, but giant cells and fibroblasts were present. With respect to collagen, the heterogenic mesh remained structurally unchanged at 90 days, while new collagen fibers were observed in the allogeneic group from day 7. CONCLUSION: The immunological outcomes of heterogenic and allogeneic ADM mesh are different. Heterogenic mesh induces a chronic inflammatory reaction at day 30 after implantation, and maintains its original form longer. Allogeneic mesh is associated with new collagen generation, but degrades earlier.
Subject(s)
Acellular Dermis , Biocompatible Materials , Prostheses and Implants , Surgical Mesh , Urinary Bladder/immunology , Vagina/immunology , Animals , Collagen/analysis , Female , Fibroblasts , Humans , Immunohistochemistry , Inflammation , Models, Animal , Rabbits , Transplantation Tolerance/immunology , Urinary Bladder/pathology , Vagina/pathologyABSTRACT
BACKGROUND: Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR). METHODS: In this study, a new polymer-based drug delivery system, poly (l-γ-glutamylglutamine)-doxorubicin (PGG-Dox) conjugate, was studied in both drug-induced resistant human breast cancer MDA-MB-231/MDR cells and their parent human breast cancer MDA-MB-231 cells. The effect of PGG on facilitating the growth inhibition of Dox against multidrug resistant cells were investigated by evaluating the cytotoxicity of PGG-Dox conjugate, PGG/Dox unconjugated complex and free Dox on both cells. The underlying mechanisms in resistant cells were further studied via the intracellular traffic studies. RESULTS: Both conjugated and unconjugated PGG significantly increased Dox uptake, prolonged Dox retention and reduced Dox efflux in the MDA-MB-231/MDR cells. The PGG-Dox conjugate is taken up by tumor cells mainly by pinocytosis pathway, in which PGG-Dox conjugate-containing vesicles are formed and enter the cells. CONCLUSIONS: This study indicated that both polymer-drug conjugate and unconjugated complex are promising strategies of overcoming resistance of anti-tumor drugs.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Dipeptides/administration & dosage , Doxorubicin/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Dipeptides/chemistry , Doxorubicin/chemistry , Drug Delivery Systems , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Female , Humans , Polymers/administration & dosage , Polymers/chemistryABSTRACT
Giant vesicles (GVs) are used to study the structures and functions of cells and cell membranes. Electroformation is the most commonly used method for GV preparation. However, the electroformation of GVs is hindered in highly concentrated ionic solutions, limiting their application as cell models for research under physiological conditions. In this study, giant multilayer vesicles were successfully generated in physiological saline using a modified electroformation device by adding an insulating layer between the two electrode plates. The influence of the electric frequency and strength on the electroformation of GVs in physiological saline was explored, and a possible mechanism for this improvement was assessed. It has been shown that an insulating layer between the two electrodes can improve the electroformation of GVs in physiological saline by increasing the electrical impedance, which is weakened by the saline solution, thereby restoring the reduced effective electric field strength. Furthermore, macromolecular plasmid DNA (pDNA) was successfully encapsulated in the electroformed GVs of the modified device. This modified electroformation method may be useful for generating eukaryotic cell models under physiological conditions.
Subject(s)
DNA , Saline Solution , Saline Solution/analysis , Cell Membrane/chemistry , Ions/analysis , DNA/analysis , Plasmids , Unilamellar Liposomes/chemistryABSTRACT
PURPOSE: To determine the influence of physicochemical properties of lipid nanoparticles (LNPs) carrying siRNA on their gene silencing in vivo. Mechanistic understanding of how the architecture of the nanoparticle can alter gene expression has also been studied. METHODS: The effect of 3-N-[(ω-methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine (PEG-C-DMA) on hepatic distribution and FVII gene silencing was determined. FVII mRNA in hepatocytes and liver tissues was determined by Q-PCR. Hepatic distribution was quantified by FACS analysis using Cy5 labeled siRNA. RESULTS: Gene silencing was highly dependent on the amount of PEG-C-DMA present. FVII gene silencing inversely correlated to the amount of PEG-C-DMA in LNPs. High FVII gene silencing was obtained in vitro and in vivo when the molar ratio of PEG-C-DMA to lipid was 0.5 mol%. Surprisingly, PEGylation didn't alter the hepatic distribution of the LNPs at 5 h post administration. Instead the amount of PEG present in the LNPs has an effect on red blood cell disruption at low pH. CONCLUSION: Low but sufficient PEG-C-DMA amount in LNPs plays an important role for efficient FVII gene silencing in vivo. PEGylation did not alter the hepatic distribution of LNPs, but altered gene silencing efficacy by potentially reducing endosomal disruption.
Subject(s)
Factor VII/genetics , Hepatocytes/metabolism , Nanoparticles/chemistry , RNA Interference , RNA, Small Interfering/administration & dosage , Animals , Cells, Cultured , Lipids/chemistry , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Polyethylene Glycols/chemistry , Propylamines/chemistry , RNA, Messenger/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
Green space is a kind of resource welfare. The evaluation of green space equity based on green view index (GVI) is important to ensure the equitable distribution of green resources. Taking the central urban area of Wuhan as the research object, based on multi-source data such as Baidu Street View Map, Baidu Thermal Map, and satellite remote sensing images, we evaluated the equity of spatial distribution of GVI in Wuhan by using the locational entropy, Gini coefficient and Lorenz curve. The results showed that 87.6% of the points in the central urban area of Wuhan were below the level of poor green vision, which mainly concentrated in Wuhan Iron and Steel Industrial Base of Qingshan District and south of Yandong Lake. The number of points reaching an excellent level was the least (0.4%), mainly concentrated around the East Lake. The overall Gini coefficient of GVI in the central urban area of Wuhan was 0.49, which indicated that the distribution of GVI was heterogeneous. The Gini coefficient of Hongshan District was the largest at 0.64, indicating a huge gap in the distribution of GVI, while the Gini coefficient of Jianghan District was the smallest at 0.47, with a large gap in the distribution. The central urban area of Wuhan had the most low-entropy areas for 29.7% and the least high-entropy areas for 15.4%. There were two-level differences in entropy distribution within Hongshan District, Qingshan District, and Wuchang District. The nature of land use and the role of linear greenery were the main factors affecting the equity of green space in the study area. Our results could provide theoretical basis and planning reference for optimizing urban green space layout.
Subject(s)
Industry , Parks, Recreational , Cities , Lakes , SteelABSTRACT
PURPOSE: To investigate the effect of 4 kinds of prosthodontic materials on masticatory and gingival function. METHODS: A total of 167 patients with dental defects who underwent prosthodontic treatment from October 2019 to January 2022 were collected. They were randomly divided into 4 groups with 41 cases in the pure titanium group, 40 cases in the cobalt-chromium alloy group, 43 cases in the nickel-chromium alloy group and 43 cases in the zirconium dioxide group. The curative effect and satisfaction degree after 6 months of treatment in 4 groups were recorded and compared. The masticatory function (chewing efficiency, bite force), gingival function[plaque index(PLI), gingival index(GI) and sulcus bleeding index(SBI)], gingival crevicular fluid inflammation-related indicators[tumor necrosis factor alpha(TNF-α), interleukin-6(IL-6), aspartate aminotransferase(AST) and alkaline phosphatase (alkaline phosphatase, ALP)] before and after treatment were measured and compared in 4 groups. Statistical analysis was performed with SPSS 20.0 software package. RESULTS: There was no significant difference in curative effect in 4 groups(Pï¼0.05). Before and after treatment, there was no significant difference in mastication efficiency and bite force in 4 groups(Pï¼0.05). Before treatment, there was no significant difference in PLI, GI, SBI, gingival crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(Pï¼0.05). Compared with before treatment, PLI, GI and SBI in 4 groups were decreased after treatment (Pï¼0.05), and the decrease was in the order of cobalt-chromium alloy group≈nickel-chromium alloy groupï¼pure titanium groupï¼zirconia dioxide group. Before treatment, there was no significant difference in the weight of gingival crevicular fluid, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(Pï¼0.05). The crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid were significantly increased(Pï¼0.05), and the increase was in the order of zirconia groupï¼pure titanium groupï¼cobalt-chromium alloy group≈nickel-chromium alloy group. There was no significant difference in restoration integrity and color satisfaction in 4 groups(Pï¼0.05), but there was significant difference in marginal fitness and sensitivity satisfaction in 4 groups(Pï¼0.05). CONCLUSIONS: Pure titanium, cobalt-chromium alloy, nickel-chromium alloy and zirconium dioxide can be used for the treatment of dentition defects, and they all can obtain satisfactory chewing function. In addition, zirconium dioxide restoration has the effect of improving gingival function and inflammation-related indicators of gingival crevicular fluid with a broader application prospect.
Subject(s)
Interleukin-6 , Tumor Necrosis Factor-alpha , Humans , Alkaline Phosphatase , Prosthodontics , Titanium , Gingival Crevicular Fluid , Chromium Alloys , InflammationABSTRACT
Aerobic vaginitis (AV) is a gynecological disease associated with vaginal flora imbalance. The nonselective bactericidal nature of antibiotics and low customization rate of probiotic supplementation in existing treatments lead to AV recurrence. Here, a drug delivery strategy is proposed that works with the changing dynamics of the bacterial flora. In particular, a core-shell nanogel (CSNG) is designed to encapsulate prebiotic inulin and antimicrobial peptide Cath 30. The proposed strategy allows for the sequential release of both drugs using gelatinase produced by AV pathogenic bacteria, initially selectively killing pathogenic bacteria and subsequently promoting the proliferation of beneficial bacteria in the vagina. In a simulated infection environment in vitro, the outer layer of CSNGs, Cath 30 is rapidly degraded and potently killed the pathogenic bacterium Staphylococcus aureus at 2-6 h. CSNGs enhances proliferation of the beneficial bacterium Lactobacillus crispatus by more than 50% at 24 h. In a rat AV model, the drug delivery strategy precisely regulated the bacterial microenvironment while controlling the inflammatory response of the vaginal microenvironment. This new treatment approach, configured on demand and precisely controlled, offers a new strategy for the treatment of vaginal diseases.
Subject(s)
Vaginitis , Vaginosis, Bacterial , Female , Humans , Animals , Rats , Vaginosis, Bacterial/drug therapy , Vaginosis, Bacterial/microbiology , Nanogels , Vaginitis/drug therapy , Vaginitis/microbiology , Vagina , Bacteria , Bacteria, Aerobic , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , SterilizationABSTRACT
OBJECTIVE: To evaluate the therapeutic effect and influence factors of silicone pessary in treatment of pelvic organ prolapse (POP). METHODS: From October 2005 to October 2010, 132 with symptomatic POP managed by pessary were enrolled in this retrospective study. Validated prolapse quality of life questionnaire (pelvic floor distress inventory short form 20, PFDI-20), pelvic floor impact questionnaire short form 7 (PFIQ-7) and the patients' satisfaction degree were used to evaluate the therapeutic effect. Clinical characteristic of the patients with successful using for more than 6 months (successful fitting group), giving up within 6 months (giving up group), unsuccessful fitting (unsuccessful fitting group) were compared. Factors influencing satisfaction degree and causing discontinuation were investigated. RESULTS: One hundred and six among 132 (106/132, 80.3%) patients were in successful fitting group, 26 (26/132, 19.7%) patients were in the unsuccessful fitting group. In the successful fitting group, 86.8% (92/106) patients were followed up, the median follow-up time was 12.5 months. And 78.3% (72/92) patients continued to use pessary with the wearing time ranged 3 - 69 months; 21.7% (20/92) patients discontinued with the wearing time ranged 1 - 38 month, 14 patients (14/20) gave up in the initial 6 months. The median scores of PFDI-20 and PFIQ-7 questionnaires before pessary use were 50.0 and 47.6, which decreased to 8.9 and 0.0 after pessary use (P < 0.05). And 87.1% (61/70) patients were satisfied. There was no significantly difference among 3 groups on clinical characteristics, such as age, body mass index (BMI), pelvic surgery and so on (P > 0.05). The main factor influencing satisfaction degree and causing discontinuation was difficulties in placing and removing. CONCLUSIONS: Silicone pessary is effective for patients with POP. It could relieve discomfort symptoms and improve quality of life. The main factor influencing pessary use is difficulties in placing and removing. Thus, More suggestions are needed for patients in the initial 6 months.
Subject(s)
Pelvic Organ Prolapse/therapy , Pessaries , Quality of Life , Aged , Female , Humans , Middle Aged , Patient Satisfaction , Pelvic Organ Prolapse/pathology , Retrospective Studies , Severity of Illness Index , Silicones , Surveys and Questionnaires , Treatment Outcome , Urinary Incontinence/etiology , Uterine Prolapse/therapy , Vagina/anatomy & histology , Vagina/pathology , Vaginal Discharge/etiologyABSTRACT
Bacterial infections from biomedical devices pose a great threat to the health of humans and thus place a heavy burden on society. Therefore, developing efficient antibacterial surfaces has attracted much attention. However, it is a challenge to identify or develop a combination that efficiently integrates multiple functions via topological tailoring and on-demand function-switch via non-contact and noninvasive stimuli. To resolve this issue, a highly hydrophilic comb polymer brush was constructed here based on supramolecular host-guest recognition. Azobenzene (azo)-modified antifouling and antibacterial polymers were incorporated into cyclodextrin (CD)-modified antifouling polymer brushes grafted on the surface. The surface thus obtained possessed excellent antifouling performance with a low bacterial density of â¼6.25 × 105 cells per cm2 after 48 h and exhibited a high efficiency of â¼88.2% for killing bacteria. Besides, irradiation with UV light resulted in the desorption of the azo-polymers and a release of â¼85.1% attached bacteria. Irradiating visible light led to the re-adsorption of azo-polymers, which regenerated the fresh surface; the process could be repeated for at least three cycles, and the surface still maintained low bacterial attachments with a cell density of â¼7.10 × 105 cells per cm2, high sterilization efficiency of â¼93.8%, and a bacteria release rate of â¼83.1% in the 3rd cycle. The photo-switchable antibacterial surface presented in this research will provide new insights into the development of smart biomedical surfaces.
Subject(s)
Bacterial Infections , Polymers , Anti-Bacterial Agents/pharmacology , Bacteria , Humans , Hydrophobic and Hydrophilic InteractionsABSTRACT
HMGB1 is an inflammatory factor produced by macrophages after liver injury, which plays a key role in promoting NASH progression and further developing into liver fibrosis and cirrhosis. In this study, a mannose-modified HMGB1-siRNA loaded stable nucleic acid lipid particle delivery system (mLNP-siHMGB1) was constructed to target liver macrophages with mannose receptor mediation, thereby silencing HMGB1 protein expression and treating NASH. We also examined the effect of co-administration with docosahexaenoic acid (DHA), a kind of unsaturated fatty acid, on NASH. The results showed that mLNP-siHMGB1 could target macrophages through mannose receptors, effectively silence HMGB1 gene, reduce the release of HMGB1 protein in the liver, regulate liver macrophages to be an anti-inflammatory M2 phenotype, effectively reduce hepatic lobular inflammation and bullous steatosis in the liver, and restore the liver function of NASH model mice to a normal level. After 8 weeks of combined treatment with mLNP-siHMGB1 and DHA, the liver function of NASH model mice recovered rapidly and the hepatic steatosis returned to normal level. In view of inflammation, a key factor in the progression of NASH, we provided an actively targeted siRNA delivery system in this study, and clarified the important role of the delivery system in phenotypic regulation of liver macrophages in NASH. In addition, we also demonstrated the effectiveness of DHA co-administration in NASH treatment. This study provided a useful idea and scientific basis for the development of therapeutic strategies for NASH in the future.
Subject(s)
HMGB1 Protein , Non-alcoholic Fatty Liver Disease , Animals , Disease Models, Animal , HMGB1 Protein/metabolism , Inflammation/pathology , Liposomes , Liver/metabolism , Liver Cirrhosis/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Nanoparticles , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA, Small Interfering/therapeutic useABSTRACT
Formulating drugs into amorphous solid dispersions (ASDs) represents an attractive means to enhance the aqueous solubility of drugs. Furthermore, water-soluble polymers have proven highly advantageous for stabilizing supersaturated solutions of ASDs. However, the performance and mechanism of various polymers in stabilizing supersaturated drug solutions have not been well-studied. The aim of this study was to investigate the effects of different commercial polymers on the dissolution behaviors and supersaturation stabilization of the ASDs and to further explore the mechanism of polymer mediated supersaturation maintenance by studying the crystallization behaviors of the ASDs. In this study, nimodipine (NMD) was used as a model drug because of its poor water-solubility and fast crystallization rate in aqueous solution, and three polymers polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP VA), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) was selected as the drug carriers to form the ASDs with NMD. Solid-state characterizations of the ASDs confirmed the amorphous state of the ASD systems. ASDPVP VA demonstrated superior supersaturation maintenance in dissolution experiments compared to the other two ASD systems. Among the polymers tested, PVP VA most efficiently maintained dissolution of NMD and prevented its crystallization from the supersaturated solution. The ability of PVP VA to most-effectively maintain supersaturation of the drug was manifested by inhibition of crystal nucleation rather than inhibition of crystal growth following nucleation. These results suggest that nucleation inhibition was instrumental in enabling the polymer-mediated supersaturation maintenance, at least with NMD.
Subject(s)
Nimodipine , Polymers , Crystallization , Humans , Polymers/chemistry , Povidone/chemistry , SolubilityABSTRACT
PURPOSE: To investigate the effects of different surface treatments and adhesive self-etch functional monomers on the immediate repair bond strength and integrity of the repaired resin composite interface. METHODS: Ninety-eight resin composite blocks made of a nanohybrid resin composite were randomly divided into seven groups, each with 14 blocks, including positive control group: non-conditioned surface, Group A1: Gluma Comfort Bond, Group A2: Gluma Comfort Bond and sandblasting, Group B1: Tokuyama Bond Force IITM adhesive system, Group B2: Tokuyama Bond Force IITM adhesive system and sandblasting, Group C: polishing, and Group D: sandblasting. Resin composite identical to the substrate was applied and the repaired specimens were subjected to shear bond strength (SBS) testing. Representative samples from all groups received scanning electron microscopy and surface profilometry to determine their mode of failure. The data were processed with SPSS 20.0 software package. RESULTS: SBS of Group D was significantly higher than that of positive control group (P<0.05). SBS of Group A1, A2, B1 and B2 was significantly higher than that of Group C and D (P<0.05). Comparison of SBS among Group B1, D and A1 showed no significant difference(P>0.05). SBS between Group B2 and positive control group had no significant difference(P>0.05). Except specimens with sandblasting and the use of TBF II system, SBS of positive control group was significantly higher than that of Group A1 and C(P<0.05). The polished specimens had significantly more adhesive failures than those with sandblasted surfaces (P<0.05). Specimens treated with polishing and Gluma Comfort Bond showed significantly more adhesive failures than those treated with polishing and TBF II system (P<0.05). The sandblasted surfaces conditioned with TBF II showed significantly more cohesive failures than those treated with polishing and TBF II (P<0.05). The sandblasted specimens provided significantly more irregular and rougher surface finish than the polishing technique (P<0.05). CONCLUSIONS: Sandblasting of the composite substrate and the use of TBF II adhesive system shows the highest repair bond strength, higher adhesive interfacial failures and fewer cohesive failures; however, it is noteworthy that the composite substrate types yield statistically higher food residue rate, which results in poor oral hygiene maintenance. Therefore, the application of this repair protocol should match up with correct oral health behaviors.
Subject(s)
Dental Bonding , Composite Resins , Dental Stress Analysis , Materials Testing , Microscopy, Electron, Scanning , Resin Cements , Shear Strength , Surface PropertiesABSTRACT
Lipid vesicle is spherical membranous structure with a concave surface on the inside. When a beam of light illuminates a lipid vesicle, the light reflected from the vesicular concave membrane can be focused to have higher intensity and generate enhanced effects. By observing and simulating light reflected from giant unilamellar vesicles (GUVs), the intensity distribution of the light reflected from a spherical concave lipid membrane was investigated. The reflected light had focused characteristics. Its intensity was concentrated 10,000 times and even exceeded the intensity of incident light in a confined region, creating another effective light source in the lipid vesicle. The fluorescence quenching of sulfo-Cy5 encapsulated in spherical GUVs was stronger than that of the outside solution when irradiated by a 632.8â¯nm laser. When irradiated with ultraviolet light C (UVC), the damage to plasmid DNA encapsulated with spherical GUVs was greater than that of pure plasmid DNA solution and plasmid DNA mixed with lipid membrane fragments. Therefore, in addition to the effects of incident light, the focused light reflected from GUVs could generate incremental effects on encapsulated photoreactive materials if the spherical structure of the lipid membrane was maintained. These results proved that concave lipid membranes of spherical vesicles can focus light and utilize it to generate enhanced effects. The capability of light focusing and its influence on DNA may provide new insights for understanding the function of lipid membranes in cellular life.
Subject(s)
Lipid Bilayers/chemistry , Lipids/chemistry , Ultraviolet Rays , Unilamellar Liposomes/chemistry , Fluorescent Dyes/analysis , Particle Size , Surface PropertiesABSTRACT
"Calcium hydroxide [Ca(OH)2]" is a medicament frequently used for antimicrobial purposes in endodontic procedures, or it is used as a toxic-waste adsorbent in industry. Ca(OH)2 particles produced through conventional methods are size untunable and have a wide size distribution and polygonal shape. In this paper, a novel and facile approach involving template-mediated synthesis and two-step ion exchange is proposed for uniform size Ca(OH)2 composite particles generation. "Sodium-alginate (Na-alginate)" was used as a precursor, and monodisperse Na-alginate emulsions were formed through needle droplet or droplet microfluidic technology. After the first ion exchange step with the Ca2+ ions, "calcium-alginate (Ca-alginate)" particles were obtained. The Ca-alginate particles were intermediate reaction products and were designed to be the templates for ensuring the spherical shape and size of products. The OH- ions were used for the second ion exchange step to fabricate Ca(OH)2 composite particles. The results revealed that the Ca(OH)2 composite particles were size tunable, had a spherical shape, and were monodisperse (with a relative standard deviation of less than 8%). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay revealed that the Ca(OH)2 composite particles were potential biocompatible materials.
ABSTRACT
Photothermal therapy (PTT) is a powerful technique for tumor ablation. However, there is a problem that PTT cannot accurately locate the tumor site, so it is easy to cause heat damage to the surrounding normal tissues. In this study, PEGylated amorphous manganese dioxide (MnO2) coated polydopamine (PDA) core-shell nanoparticles (PDA@MnO2-PEG) with regular morphology and uniform dimensions were prepared for acid-sensitive magnetic resonance imaging-guided tumor photothermal therapy. The results showed that amorphous MnO2 shell provided markedly acid-sensitive T1-weighted magnetic resonance imaging (MRI). The relaxation rate (r1 value) of PDA@MnO2-PEG in pH=7.4 was measured to be 0.310 mM-1·S-1, while that in pH=6 became 4.364 mM-1·S-1. In mice tumor models, MRI of tumors exhibited dramatically whitening effects compared with the signal before injection. Besides, the in vivo experiments revealed that the tumors in PTT group with PDA@MnO2-PEG injection and NIR laser irradiation were almost eliminated within 14 days, indicating the effective photothermal therapy of tumor generated by the PDA core. In conclusion, we successfully synthesized amorphous MnO2 coated PDA core-shell nanoparticles with the function of acid-sensitive magnetic resonance imaging guided photothermal therapy, which provide a new approach for improving the effect of photothermal therapy of tumors.
Subject(s)
Nanoparticles , Animals , Indoles , Magnetic Resonance Imaging , Manganese Compounds , Mice , Oxides , PolymersABSTRACT
This study is intended to develop and evaluate a novel, highly water-soluble polymer drug conjugate poly(l-γ-glutamyl-l-carbocisteine)-paclitaxel (PGSC-PTX) which can trigger drug release in tumor acidic microenvironment and improve the therapeutic index of paclitaxel (PTX). PGSC-PTX is formed by introducing an additional carbocisteine into each glutamic side chain of poly(l-glutamic acid)-paclitaxel (PGA-PTX) conjugate. PGSC-PTX self-assembles into nanoparticles, whose size remains in the range of 15-20nm. PGSC-PTX demonstrated sensitive to pH and released PTX rapidly in low pH. PGSC-PTX shows significant in vitro cytotoxicity to NH460 cancer cell line, which has less toxic and side effect of than PTX. Meanwhile, the hemolytic test indicated that the nanoparticles could be used for intravenous injection. It was concluded that the maximum tolerated dose of PGSC-PTX achieved to be 250mg PTX/kg, which is extremely maximum tolerated providing a significant foundation in the clinical research.