Comparison study of surface-initiated hydrogel coatings with distinct side-chains for improving biocompatibility of polymeric heart valves.

Polymeric heart valves (PHVs) present a promising alternative for treating valvular heart diseases with satisfactory hydrodynamics and durability against structural degeneration. However, the cascaded coagulation, inflammatory responses, and calcification in the dynamic blood environment pose significant challenges to the surface design of current PHVs. In this study, we employed a surface-initiated polymerization method to modify polystyrene-block-isobutylene-block-styrene (SIBS) by creating three hydrogel coatings: poly(2-methacryloyloxy ethyl phosphorylcholine) (pMPC), poly(2-acrylamido-2-methylpropanesulfonic acid) (pAMPS), and poly(2-hydroxyethyl methacrylate) (pHEMA). These hydrogel coatings dramatically promoted SIBS's hydrophilicity and blood compatibility at the initial state. Notably, the pMPC and pAMPS coatings maintained a considerable platelet resistance performance after 12 h of sonication and 10 000 cycles of stretching and bending. However, the sonication process induced visible damage to the pHEMA coating and attenuated the anti-coagulation property. Furthermore, the in vivo subcutaneous implantation studies demonstrated that the amphiphilic pMPC coating showed superior anti-inflammatory and anti-calcification properties. Considering the remarkable stability and optimal biocompatibility, the amphiphilic pMPC coating constructed by surface-initiated polymerization holds promising potential for modifying PHVs.

Antimicrobial dental composites with K18-methyl methacrylate and K18-filler.

OBJECTIVE: To determine the effects of using K18-methyl methacrylate (K18-MMA) and K18-Filler on composite cure, esthetic, mechanical, polymerization shrinkage, and antimicrobial properties. METHODS: K18-MMA (0-20% w/w) was used to replace TEGDMA in a 70:30 Bis-GMA:TEGDMA composite filled to 70% w/w with barium glass or K18-Filler. Composite degree of cure (Rockwell15T hardness and near Infrared FTIR), hydrophilicity (contact angle measurements), translucency (transparency parameter measurements, TP), mechanical (3-point bend test), polymerization shrinkage (volumetric shrinkage and shrinkage stress), and antimicrobial properties (colony counting assay) against Streptococcus mutans, Streptococcus sanguinis, and Candida albicans were determined. RESULTS: All experimental groups had comparable degrees of cure (near Infrared FTIR and Rockwell15T Hardness), TP, moduli, polymerization volumetric shrinkages and shrinkage stresses to those of controls (Bonferroni corrected p > 0.0018). Only one group (15% K18-MMA+K18-Filler) had significantly different (lower) contact angles as compared to that of controls (Bonferroni corrected p < 0.0018). Most of the K18-Filler-containing composites had significantly lower ultimate transverse strengths (UTS) than controls (Bonferroni corrected p < 0.0018). Controls had significantly greater S mutans colony counts than 15% and 20% w/w K18-MMA+K18-Filler groups, and greater S sanguinis and C albicans colony counts than K18-containing groups. Of the composites with that provided significant antimicrobial properties against S. mutans, S. sanguinis, and C. albicans, only the 20% K18-MMA+K18-Filler group had significantly lower UTS than controls. SIGNIFICANCE: Composites with K18-MMA and K18-Filler with comparable physical properties to control composites and significant antimicrobial properties have been developed. K18-MMA and K18-Filler seem to be suitable for incorporation into commercial dental resins.

Novel hydrolytic resistant antibacterial monomers for dental resin adhesive.

OBJECTIVES: To evaluate the properties of novel hydrolytic resistant antibacterial monomers and to determine the properties of resin adhesives containing these monomers. METHODS: Methacrylamide-based QAC (Quaternary Ammonium Compound) monomers, 1-(11-Methacryla-midoundecyl)pyridine-1-ium bromide (MAUPB) and 1-(12-Methacryl-amidododecyl)pyridine-1-ium bromide (MADPB), and their methacrylate-derivatives, N-(1-Methacryloylundecanyl)pyridinium bromide (MUPB) and N-(1-Methacryloyldodecanyl)pyridinium bromide (MDPB), were synthesized and characterized. The minimum inhibitory (MIC) and bactericidal (MBC) concentrations were determined against S.mutans and E.faecalis. Cytotoxicity of unpolymerized monomers were evaluated using L-929 and MDPC-23. Each monomer was incorporated into experimental resins (BisGMA/TEGDMA/CQ/EDMAB or BisGMA/HEMA/CQ/EDMAB) at 10wt%. FTIR Spectra were collected for degree of conversion (DC%) measurement. Bacterial attachment on resin disks were determined by fluorescent microscope. Mechanical properties of experimental resins were evaluated by flexural strength & modulus and shear bond strength testing. RESULTS: The antibacterial activity of MDPB≥MUPB>MADPB>MAUPB. The TC50 of MAUPB> MADPB>MUPB >MDPB. Incorporation of MAUPB in BisGMA/TEGDMA-based resin, had no significant effect on DC%, while significantly increase DC% in BisGMA/HEMA-based Resin. MUPB and MAUPB containing resins showed less viable bacterial attachment than pure resins. After 3-month storage, resins containing MAUPB illustrated higher flexural strength than their corresponding resins containing MUPB. BisGMA/HEMA-based resin containing MAUPB illustrated significantly higher resin-dentin shear bond strength than that of MUPB and pure resin. CONCLUSIONS: Methacrylamide monomer containing QAC, MAUPB, possessed antibacterial properties and superior physical and mechanical properties when incorporated in resin adhesives as compared to their corresponding methacrylate monomer, MUPB. CLINICAL SIGNIFICANCE: Methacrylamide-based QAC monomers are potentially used to formulate antibacterial hydrolytic resistant resin adhesives and enhance resin-dentin bond strength.

Novel mechanically strong and antibacterial dimethacrylate copolymers based on quaternary ammonium urethane-dimethacrylate analogues.

OBJECTIVES: This study assumed that the quaternary ammonium urethane-dimethacrylate derivative (QAUDMA-m, where m was 8, 10, 12, 14, 16, 18, and corresponded to the number of carbon atoms in the N-alkyl substituent) can be used to achieve copolymers with high mechanical performance and antibacterial activity. METHODS: Photocured copolymers of bisphenol A glycerolate dimethacrylate (Bis-GMA) 40 wt%, QAUDMA-m 40 wt%, and triethylene glycol dimethacrylate (TEGDMA) 20 wt% (BG:QAm:TEG) were characterized by the degree of conversion (DC), flexural strength (FS), flexural modulus (E), hardness (HB), and antibacterial properties (the number of bacteria colonies adhered to copolymer surfaces and inhibition zone diameter (IZD)) against Staphylococcus aureus and Escherichia coli. Reference copolymers of Bis-GMA, urethane-dimethacrylate monomer (UDMA), and TEGDMA (BG:TEG and BG:UD:TEG) were also characterized. RESULTS: The DC of BG:QAm:TEGs ranged from 0.59 to 0.68, HB from 83.84 to 153.91 MPa, FS from 50.81 to 74.47 MPa, and E from 1986.74 to 3716.68 MPa. The number of S. aureus and E. coli bacteria adhered to BG:QAm:TEG surfaces was from 0 (no bacteria observed) to 6.47 and 4.99 log(CFU/mL), respectively. IZD was from 10 and 5 mm (no inhibition zone) to 23 and 21 mm, respectively. Three copolymers: BG:QA8:TEG, BG:QA10:TEG, and BG:QA12:TEG had similar or better mechanical properties than the reference copolymers, but unlike them, they showed high antibacterial activity against both bacteria strains. SIGNIFICANCE: The obtained copolymers can offer a good, mechanically efficient, bioactive alternative to BG:TEG and BG:UD:TEG copolymers. The use of such materials can help to make progress in dental health care.

Effect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model.

Cancer is a leading cause of mortality globally. Despite remarkable improvements in cancer-treatment approaches, disease recurrence and progression remain major obstacles to therapy. While chemotherapy is still a first-line treatment for a variety of cancers, the focus has shifted to the development and application of new approaches to therapy. Nevertheless, the relationship between immune response, neoplastic diseases and treatment efficiency is not fully understood. Therefore, the aim of the study was to investigate the immunopharmacological effects of methacrylic acid homopolymer in an in vivo tumor model. MATERIALS AND METHODS: Monomeric methacrylic acid was used to synthesize polymers. Methacrylic acid was polymerized in dioxane in the presence of 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid. To study the molecular weight characteristics of PMAA by GPC, carboxyl groups were preliminarily methylated with diazomethane. An experimental cancer model was obtained by grafting RMK1 breast cancer cells. The serum levels of IL-6, IL-10, IL-17, transforming growth factor ß1 (TGF-ß1), and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: The effect of PMAA on the serum concentrations of several cytokines was studied upon its single administration to laboratory animals in early neoplastic process. The IL-6, IL-17 and TGF-ß1 concentrations were found to change significantly and reach the level observed in intact rats. The IL-10 concentration tended to normalize. CONCLUSION: The positive results obtained are the basis for further studies on the effect of methacrylic-acid polymers with different molecular-weight characteristics on the neoplastic process.

Preparation of Bis-GMA free dental resin composites with anti-adhesion effect against Streptococcus mutans using synthesized fluorine-containing methacrylate (DFMA).

With purpose of preparing Bis-GMA free dental resin composites (DRCs) with anti-adhesion effect against Streptococcus mutans (S. mutans), a new fluorinated dimethacrylate (DFMA) was synthesized and used as base resin of DRCs. Two reactive diluents TEGDMA and SR833s were mixed with DFMA separately to prepare resin matrixes. After mixing with inorganic fillers, two DFMA based DRCs were obtained and named as DT (DFMA/TEGDMA) and DS (DFMA/SR833s) according to the resin matrix composition. Bis-GMA based DRC (BT) was used as control. The double bond conversion (DC), bacteria adhesion, mucin adsorption, contact angle, surface free energy, volumetric shrinkage (VS), shrinkage stress (SS), water sorption (WS) and solubility (SL), flexural strength (FS) and modulus (FM) before and after water immersion were investigated, and all the results were statistically analyzed with ANOVA analysis. The results showed that DT and DS had comparable (ρ > 0.05) surface free energy which was lower than that of BT (ρ < 0.05). Compared with BT, with the same surface roughness (ρ > 0.05), less amount of S. mutans was accumulated on the surface of DT and DS (ρ < 0.05). In all DRCs, the DS had the best resistance to mucin adsorption (ρ < 0.05) due to its high hydrophobicity. Compared with BT, both DFMA based DRCs had advantages such as lower VS and SS (ρ < 0.05), lower WS and SL (ρ < 0.05), and better water resistance. The DS, which had antibacterial adhesion effect, mucin adsorption resistance, lowest VS and SL (ρ < 0.05), and the highest FS and FM no matter before or after water immersion (ρ < 0.05) was considered to have the best comprehensive properties in all DRCs.

Novel Antibacterial Copolymers Based on Quaternary Ammonium Urethane-Dimethacrylate Analogues and Triethylene Glycol Dimethacrylate.

The growing scale of secondary caries and occurrence of antibiotic-resistant bacterial strains require the development of antibacterial dental composites. It can be achieved by the chemical introduction of quaternary ammonium dimethacrylates into dental composites. In this study, physicochemical and antibacterial properties of six novel copolymers consisting of 60 wt. % quaternary ammonium urethane-dimethacrylate analogues (QAUDMA) and 40 wt. % triethylene glycol dimethacrylate (TEGDMA) were investigated. Uncured compositions had suitable refractive index (RI), density (dm), and glass transition temperature (Tgm). Copolymers had low polymerization shrinkage (S), high degree of conversion (DC) and high glass transition temperature (Tgp). They also showed high antibacterial effectiveness against S. aureus and E. coli bacterial strains. It was manifested by the reduction in cell proliferation, decrease in the number of bacteria adhered on their surfaces, and presence of growth inhibition zones. It can be concluded that the copolymerization of bioactive QAUDMAs with TEGDMA provided copolymers with high antibacterial activity and rewarding physicochemical properties.

Single-Cellular Biological Effects of Cholesterol-Catabolic Bile Acid-Based Nano/Micro Capsules as Anti-Inflammatory Cell Protective Systems.

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic ß-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules' images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules' thermal and chemical stability assays were also assessed to ascertain an association between capsules' stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.

Eudragit, a Nifty Polymer for Anticancer Preparations: A Patent Review.

BACKGROUND: Polymers are the backbone of modern pharmaceutical formulations and drug delivery technologies. Polymers that may be natural, synthetic, or semisynthetic are used to control the release of drugs in a pre-programmed fashion. The drug delivery systems are mainly prepared to enhance the bioavailability, site-specific release, sustained release, controlled release, i.e., to modify the release of drug from dosage form may be a tablet, capsule, etc. Objectives: The objective of the present study is to overview the recent patents concerning the application of eudragit in the prevention of cancer and other ailments. Eudragit polymers are polymethacrylates and may be anionic, cationic, or non-ionic polymers of methacrylic acid, dimethylaminoethyl methacrylates, and methacrylic acid esters in varying ratios. Eudragit is available in various grades with solubilities at different pH, thus helping the formulators design the preparation to have a well-defined release pattern. METHODS: In this review, patent applications of eudragit in various drug delivery systems employed to cure mainly cancer are covered. RESULTS: Eudragit has proved its potential as a polymer to control the release of drugs as coating polymer and formation of the matrix in various delivery systems. It can increase the bioavailability of the drug by site-specific drug delivery and can reduce the side effects/toxicity associated with anticancer drugs. CONCLUSION: The potential of eudragit to carry the drug may unclutter novel ways for therapeutic intercessions in various tumors.

Fluoroquinolones Suppress TGF-ß and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment.

BACKGROUND: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-ß) and phorbol 12-myristate 13-acetate (PMA) stimulation. EXPERIMENTAL APPROACHES: Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-ß and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-ß and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-ß and PMA-induced cell migration via p38 and cyclic AMP signaling pathways. CONCLUSIONS AND IMPLICATIONS: Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment.

The use of optical differential scanning calorimetry to investigate ibuprofen miscibility in polymeric films for topical drug delivery.

Understanding drug miscibility in pharmaceutically relevant systems is essential for the development and optimisation of pharmaceutical dosage forms. This is particularly true for film forming systems which are designed to become supersaturated with drug, following application on the skin surface, whilst maintaining the physical stability of the drug for a suitable period to enhance drug delivery. For such formulations, chemical penetration enhancers as well as the drug are absorbed from the formulation into the skin, making understanding drug delivery from the films challenging. This study investigated the use of an optical differential scanning calorimetry (DSC) to understand drug miscibility in polymeric film forming systems and explain drug transport behaviour from film forming formulations, containing ibuprofen, a copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (Eudragit® E, EuE), a copolymer based on ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups (Eudragit® RS, EuRS) and a copolymer based on methacrylic acid and methyl methacrylate (Eudragit® S, EuS), with and without the chemical penetration enhancer propylene glycol, across a model membrane. The optical DSC enabled the rapid screening of not only drug-polymer miscibility, but also drug-vehicle miscibility, while considering both the melting-point depression and melting enthalpy of the drug due to the presence of the polymer/polymer-based vehicle, obtained via thermal analysis by structural characterisation (TASC) and DSC analysis, respectively. The results obtained enable the polymers studied to be ranked in the order of EuE > EuRS > EuS, with EuE being more miscible with ibuprofen, and the incorporation of a penetration enhancer in the film forming system formulation was found to increase ibuprofen solubility in EuE- and EuRS- based films. The drug-polymer/vehicle miscibility information obtained via optical DSC provided understanding of drug transport from film forming systems with the higher miscibility of ibuprofen with EuE reducing drug transport through decreasing drug saturation in the film. The higher drug transport from films containing EuRS and EuS could also be linked to drug miscibility with the polymer and showed dependence on ibuprofen loading in the formulation. Overall optical DSC has been demonstrated to be a valuable tool for determining drug-vehicle miscibility for pharmaceutical product development.

Is there an optimal method to detach Candida albicans biofilm from dental materials?

Introduction. Candida albicans can produce a complex, dynamic and resistant biofilm on the surface of dental materials, especially denture base acrylic resins and temporary soft liners. This biofilm is the main aetiological factor for denture stomatitis, an oral inflammatory condition characterized by chronic and diffuse erythema and oedema of the denture bearing mucosa.Gap Statement. There is no consensus in the literature regarding the best method to detach biofilms from dental materials. In order to assess the antifungal efficacy of new materials and treatments, the biofilm needs to be properly detached and quantified.Aim. This study compared different methods of detaching C. albicans biofilm from denture base acrylic resin (Vipi Cril) and temporary soft liner (Softone) specimens.Methodology. Specimens of each material were immersed in an inoculum of C. albicans SC5314 and remained for 90 min in orbital agitation at 75 r.p.m. and 37 °C. After the removal of non-adherent cells, the specimens were immersed in RPMI-1640 medium for 48 h. Biofilm formation was evaluated with confocal laser scanning microscopy (n=5). Then, other specimens (n=7) were fabricated, contaminated and immersed in 3 ml of sterile phosphate-buffered saline (PBS) and vortexed or sonicated for 1, 2, 5, or 10 min to detach the biofilm. The quantification of detached biofilm was performed by colony-forming unit (c.f.u.) ml-1 count. Results were submitted to one-way analysis of variance (ANOVA)/Tukey HSD test (α=0.05).Results. A mature and viable biofilm was observed on the surfaces of both materials. For both materials, there was no significant difference (P>0.05) among detachment methods.Conclusion. Any of the tested methods could be used to detach C. albicans biofilm from hard and soft acrylic materials.

Rapamycin modulates pulmonary pathology in a murine model of Mycobacterium tuberculosis infection.

Tuberculosis (TB) treatment regimens are lengthy, causing non-adherence to treatment. Inadequate treatment can lead to relapse and the development of drug resistance TB. Furthermore, patients often exhibit residual lung damage even after cure, increasing the risk for relapse and development of other chronic respiratory illnesses. Host-directed therapeutics are emerging as an attractive means to augment the success of TB treatment. In this study, we used C3HeB/FeJ mice as an experimental model to investigate the potential role of rapamycin, a mammalian target of rapamycin inhibitor, as an adjunctive therapy candidate during the treatment of Mycobacterium tuberculosis infection with moxifloxacin. We report that administration of rapamycin with or without moxifloxacin reduced infection-induced lung inflammation, and the number and size of caseating necrotic granulomas. Results from this study strengthen the potential use of rapamycin and its analogs as adjunct TB therapy, and importantly underscore the utility of the C3HeB/FeJ mouse model as a preclinical tool for evaluating host-directed therapy candidates for the treatment of TB.

Immune Effect Regulated by the Chain Length: Interaction between Immune Cell Surface Receptors and Synthetic Glycopolymers.

Glycopolymer-based drugs for immunotherapy have attracted increasing attention because the affinity between glycans and proteins plays an important role in immune responses. Previous studies indicate that the polymer chain length influences the affinity. In the studies on enhancing the immune response by glycans, it is found that both oligosaccharides and long-chain glycopolymers work well. However, there is a lack of systematic studies on the immune enhancement effect and the binding ability of oligomers and polymers to immune-related proteins. In this paper, to study the influence of the chain length, glycopolymers based on N-acetylglucosamine with different chain lengths were synthesized, and their interaction with immune-related proteins and their effect on dendritic cell maturation were evaluated. It was proved that compared with l-glycopolymers (degree of polymerization (DP) > 20), s-glycopolymers (DP < 20) showed better binding ability to the dendritic cell-specific ICAM-3-grabbing nonintegrin protein and the toll-like receptor 4 and myeloid differentiation factor 2 complex protein by quartz crystal microbalance and molecular docking simulation. When the total sugar unit amounts are equal, s-glycopolymers are proved to be superior in promoting dendritic cell maturation by detecting the expression level of CD80 and CD86 on the surface of dendritic cells. Through the combination of experimental characterization and theoretical simulation, a deep look into the interaction between immune-related proteins and glycopolymers with different chain lengths is helpful to improve the understanding of the immune-related interactions and provides a good theoretical basis for the design of new glycopolymer-based immune drugs.

Unexpected Enhancement of Antimicrobial Polymer Activity against Staphylococcus aureus in the Presence of Fetal Bovine Serum.

Cationic and amphiphilic polymers are known to exert broad-spectrum antibacterial activity by a putative mechanism of membrane disruption. Typically, nonspecific binding to hydrophobic components of the complex biological milieu, such as globular proteins, is considered a deterrent to the successful application of such polymers. To evaluate the extent to which serum deactivates antibacterial polymethacrylates, we compared their minimum inhibitory concentrations in the presence and absence of fetal bovine serum. Surprisingly, we discovered that the addition of fetal bovine serum (FBS) to the assay media in fact enhances the antimicrobial activity of polymers against Gram-positive bacteria S. aureus, whereas the opposite is the case for Gram-negative E. coli. Here, we present these unexpected trends and develop a hypothesis to potentially explain this unusual phenomenon.

Immunopharmacological Properties of Methacrylic Acid Polymers as Potential Polymeric Carrier Constituents of Anticancer Drugs.

Cytostatic chemotherapeutics provide a classical means to treat cancer, but conventional treatments have not increased in efficacy in the past years, warranting a search for new approaches to therapy. The aim of the study was, therefore, to obtain methacrylic acid (MAA) (co)polymers and to study their immunopharmacological properties. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid (CDSPA) and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT) were used as reversible chain transfer agents. Experiments were carried out in Wistar rats. The MTT assay was used to evaluate the cytotoxic effect of the polymeric systems on peritoneal macrophages. An experimental tumor model was obtained by grafting RMK-1 breast cancer cells. Serum cytokine levels of tumor-bearing rats were analyzed. The chain transfer agents employed in classical radical polymerization substantially reduced the molecular weight of the resulting polymers, but a narrow molecular weight distribution was achieved only with CDSPA and high CPDT concentrations. Toxicity was not observed when incubating peritoneal macrophages with polymeric systems. In tumor-bearing rats, the IL-10 concentration was 1.7 times higher and the IL-17 concentration was less than half that of intact rats. Polymeric systems decreased the IL-10 concentration and normalized the IL-17 concentration in tumor-bearing rats. The maximum effect was observed for a MAA homopolymer with a high molecular weight. The anion-active polymers proposed as carrier constituents are promising for further studies and designs of carrier constituents of drug derivatives.

Mucoadhesive and mucus-penetrating interpolyelectrolyte complexes for nose-to-brain drug delivery.

Nasal administration offers a possibility of delivering drugs to the brain. In the present work, nasal drug delivery systems were designed based on cationic Eudragit® EPO (EPO) and anionic Eudragit® L100-55 (L100-55) methacrylate copolymers. Two types of nanocarriers were prepared using interpolyelectrolyte complexation between these polymers. The first type of nanoparticles was prepared by forming interpolyelectrolyte complexes between unmodified EPO and L100-55. The second type of nanoparticles was formed through the complexation between PEGylated L100-55 and EPO. For this purpose, PEGylated L100-55 was synthesized by chemical conjugation of L100-55 with O-(2-aminoethyl)polyethylene glycol. The mucoadhesive properties of these nanoparticles were evaluated ex vivo using sheep nasal mucosa. Nanoparticles based on EPO and L100-55 exhibited mucoadhesive properties towards nasal mucosa, whereas PEGylated nanoparticles were non-mucoadhesive hence displayed mucus-penetrating properties. Both types of nanoparticles were used to formulate haloperidol and their ability to deliver the drug to the brain was evaluated in rats in vivo.

Combination of irreversible electroporation with sustained release of a synthetic membranolytic polymer for enhanced cancer cell killing.

Irreversible electroporation (IRE) is used clinically as a focal therapy to ablate solid tumors. A critical disadvantage of IRE as a monotherapy for cancer is the inability of ablating large tumors, because the electric field strength required is often too high to be safe. Previous reports indicate that cells exposed to certain cationic small molecules and surfactants are more vulnerable to IRE at lower electric field strengths. However, low-molecular-weight IRE sensitizers may suffer from suboptimal bioavailability due to poor stability and a lack of control over spatiotemporal accumulation in the tumor tissue. Here, we show that a synthetic membranolytic polymer, poly(6-aminohexyl methacrylate) (PAHM), synergizes with IRE to achieve enhanced cancer cell killing. The enhanced efficacy of the combination therapy is attributed to PAHM-mediated sensitization of cancer cells to IRE and to the direct cell killing by PAHM through membrane lysis. We further demonstrate sustained release of PAHM from embolic beads over 1 week in physiological medium. Taken together, combining IRE and a synthetic macromolecular sensitizer with intrinsic membranolytic activity and sustained bioavailability may present new therapeutic opportunities for a wide range of solid tumors.

Hemocompatibility of polyzwitterion-modified titanium dioxide nanotubes.

Titanium dioxide nanotubes (TNTs) have attracted increasing interest as implantable materials due to their many desirable properties. However, their blood compatibility remains an issue. In this paper, TNTs of different diameters were modified with two types of zwitterionic polymers, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA), which were grafted onto the TNTs using ARGET-ATRP (activators regenerated by electron transfer atom transfer radical polymerization) method. Both pSBMA and pCBMA brushes coatings were found to greatly reduce adsorption of bovine serum albumin (BSA) and fibrinogen (Fib) onto the TNTs, showing excellent protein resistance. Moreover, the effects of the surface topography on the amount of protein adsorption were largely suppressed by the polyzwitterion coatings. The conformation of the protein adsorbed to the substrates was analyzed at the molecular level by Fourier-transform infrared reflection spectroscopy (FT-IR), which revealed that the BSA adsorbed on the polyzwitterion-modified TNTs adopted significantly different secondary structures from that on the virgin TNTs, whereas the conformation of the adsorbed Fib remained basically the same. The polyzwitterion-modified TNTs were found to be non-hemolytic, and platelet adhesion and activation was significantly reduced, showing excellent blood compatibility.

JNK-mediated blockage of autophagic flux exacerbates the triethylene glycol dimethacrylate-induced mitochondrial oxidative damage and apoptosis in preodontoblast.

Mitochondrial dependent oxidative stress (OS) and subsequent cell death are considered as the major cytotoxicity caused by Triethylene glycol dimethacrylate (TEGDMA), a commonly monomer of many resin-based dental composites. Under OS microenvironment, autophagy serves as a cell homeostatic mechanism and maintains redox balance through degradation or turnover of cellular components in order to promote cell survival. However, whether autophagy is involved in the mitochondrial oxidative damage and apoptosis induced by TEGDMA, and the cellular signaling pathways underlying this process remain unclear. In the present study, we demonstrated that TEGDMA induced mouse preodontoblast cell line (mDPC6T) dysfunctional mitochondrial oxidative response. In further exploring the underlying mechanisms, we found that TEGDMA impaired autophagic flux, as evidenced by increased LC3-II expression and hindered p62 degradation, thereby causing both mitochondrial oxidative damage and cell apoptosis. These results were further verified by treatment with chloroquine (autophagy inhibitor) and rapamycin (autophagy promotor). More importantly, we found that the JNK/MAPK pathway was the key upstream regulator of above injury process. Collectively, our finding firstly demonstrated that TEGDMA induced JNK-dependent autophagy, thereby promoting mitochondrial dysfunction-associated oxidative damage and apoptosis in preodontoblast.