Nanoprecipitation of polymeric nanoparticle micelles based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), for intracellular delivery applications

Biodistribution of nanoparticle-based intracellular delivery systems is mediated primarily by particle size and physicochemical properties. As such, overcoming the rapid removal of these by the reticuloendothelial system remains a significant challenge. To date, a number of copolymer nanoparticle systems based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino)ethyl methacrylate (DPA), displaying biomimetic and pH responsive properties, have been published, however these have been predominately polymersome based, whilst micelle systems have remained relatively unexplored. This study utilised nanoprecipitation to investigate the effects of solvent and buffer choice upon micelle size and polydispersity, and found using methanol produced monodisperse micelles of circa 70 nm diameter, whilst ethanol produced polydisperse systems with nanoparticles of circa 128 nm diameter. The choice of aqueous buffer, dialysis of the systems, extended storage, and exposure to a wide temperature range (5–70 °C) had no significant effect on micelle size, and the systems were highly resistant to dilution, indicating excellent colloidal stability. Optimisation of the nanoprecipitation process, post precipitation, was investigated, and model drugs successfully loaded whilst maintaining system stability. Subsequent in vitro studies suggested that the micelles were of negligible cellular toxicity, and an apparent cellular uptake was observed via confocal laser scanning microscopy. This paper presents the first report of an optimised nanoprecipitation methodology for the formation of MPC–DPA nanoparticle micelles, and in doing so achieved monodisperse systems with the size and physicochemical characteristics seen as desirable for long circulating therapeutic delivery vehicles

Development of MPC-DPA polymeric nanoparticle systems for inhalation drug delivery applications

Inhalation of nanoparticles for pulmonary drug delivery offers the potential to harness nanomedicine formulations of emerging therapeutics, such as curcumin, for treatment of lung cancer. Biocompatible nanoparticles composed of poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA) have been shown to be suitable nanocarriers for drugs, whilst N-trimethyl chitosan chloride (TMC) coating of nanoparticles has been reported to further enhance their cellular delivery efficacy; the combination of the two has not been previously investigated. Development of effective systems requires the predictable, controllable, and reproducible ability to prepare nanosystems possessing particle sizes, and drug loading capacities, appropriate for successful airway travel, lung tissue penetration, and tumour suppression. Although a number of MPC-DPA based nanosystems have been described, a complete understanding of parameters controlling nanoparticle formation, size, and morphology has not been reported; in particular the effects of differing solvents phases remains unclear. In this current study a matrix of 31 solvent combinations were examined to provide novel data pertaining to the formation of MPC-DPA nanoparticles, and in doing so afforded the selection of systems with particle sizes appropriate for pulmonary delivery applications to be loaded with curcumin, and coated with TMC. This paper presents the first report of novel data detailing the successful preparation, characterisation, and optimisation of MPC-DPA nanoparticles of circa 150 – 180 nm diameter, with low polydispersity, and a curcumin loading range of circa 2.5 – 115 µM, tunable by preparation parameters, with and without TMC coating, and thus considered suitable candidates for inhalation drug delivery applications

Drug carriers comprising amphiphilic block copolymers

An aqueous composition comprises an amphiphilic block copolymer, having a hydrophilic block comprising pendant zwitterionic groups and a hydrophobic block, and a biologically active compound associated with the polymer. The polymer is preferably in the form of micelles, and preferably the biological active is a hydrophobic drug, for instance having a calculated or experimentally determined logP of at least 1.0, where P is the octanol:water partition coefficient. The hydrophilic block is preferably formed from acrylic monomer including phosphoryicholine groups. The hydrophobic group is suitably formed from monomer which has groups which can be ionised at useful pH's, especially tertiary amine groups. Micelles may be formed by dissolving the block copolymer in aqueous solvent at a pH at which the amine groups are protonated then raising the pH to a value at which the amine groups are substantially deprotonated, whereupon micelles spontaneously form. The preformed micelles are then contacted with active, under conditions such that solubilisation of the active occurs. The active may be a water-insoluble drug, for instance for tumour treatment

Ultrasensitive strain gauges enabled by graphene-stabilized silicone emulsions

Here, an approach is presented to incorporate graphene nanosheets into a silicone rubber matrix via solid stabilization of oil‐in‐water emulsions. These emulsions can be cured into discrete, graphene‐coated silicone balls or continuous, elastomeric films by controlling the degree of coalescence. The electromechanical properties of the resulting composites as a function of interdiffusion time and graphene loading level are characterized. With conductivities approaching 1 S m−1, elongation to break up to 160%, and a gauge factor of ≈20 in the low‐strain linear regime, small strains such as pulse can be accurately measured. At higher strains, the electromechanical response exhibits a robust exponential dependence, allowing accurate readout for higher strain movements such as chest motion and joint bending. The exponential gauge factor is found to be ≈20, independent of loading level and valid up to 80% strain; this consistent performance is due to the emulsion‐templated microstructure of the composites. The robust behavior may facilitate high‐strain sensing in the nonlinear regime using nanocomposites, where relative resistance change values in excess of 107 enable highly accurate bodily motion monitoring

A Novel Inducible Prophage from Burkholderia Vietnamiensis G4 is Widely Distributed across the Species and Has Lytic Activity against Pathogenic Burkholderia.

Burkholderia species have environmental, industrial and medical significance, and are important opportunistic pathogens in individuals with cystic fibrosis (CF). Using a combination of existing and newly determined genome sequences, this study investigated prophage carriage across the species B. vietnamiensis, and also isolated spontaneously inducible prophages from a reference strain, G4. Eighty-one B. vietnamiensis genomes were bioinformatically screened for prophages using PHASTER (Phage Search Tool Enhanced Release) and prophage regions were found to comprise up to 3.4% of total genetic material. Overall, 115 intact prophages were identified and there was evidence of polylysogeny in 32 strains. A novel, inducible Mu-like phage (vB_BvM-G4P1) was isolated from B. vietnamiensis G4 that had lytic activity against strains of five Burkholderia species prevalent in CF infections, including the Boston epidemic B. dolosa strain SLC6. The cognate prophage to vB_BvM-G4P1 was identified in the lysogen genome and was almost identical (>93.5% tblastx identity) to prophages found in 13 other B. vietnamiensis strains (17% of the strain collection). Phylogenomic analysis determined that the G4P1-like prophages were widely distributed across the population structure of B. vietnamiensis. This study highlights how genomic characterization of Burkholderia prophages can lead to the discovery of novel bacteriophages with potential therapeutic or biotechnological applications

Bioactive and resorbable soybean-based biomaterials

A method of producing a soybean-based biomaterial which is suitable for use in a biomedical product, the method comprising: defatting soy flour; either prior to or at the same time as, performing a solvent extraction; to produce a biomaterial comprising variable levels of soy proteins, carbohydrates and isoflavones. The resulting biomaterials have a range of biomedical uses and are particularly desirable because of their isoflavone content. Examples of biomedical products containing the biomaterials include wound dressings; scaffolds for tissue engineering; fillers or implants for use in surgery; temporary barriers for use in dental or surgical procedures or to prevent post-surgical tissue adherence; carriers for the delivery of drugs, bioactive peptides or plasmids; anti-inflammatory agents; coatings for wound dressings or for dental, medical, surgical or veterinary devices or implants; and compositions for soothing skin or gum irritation

Smart Skins Based on Assembled Piezoresistive Networks of Sustainable Graphene Microcapsules for High Precision Health Diagnostics

The environmental impact of plastic waste has had a profound effect on our livelihoods and there is a need for future plastic-based epidermal electronics to trend toward more sustainable approaches. Infusing graphene into the culinary process of seaweed spherification produces core-shell, food-based nanocomposites with properties exhibiting a remarkably high degree of tunability. Unusually, mechanical, electrical, and electromechanical metrics all became decoupled from one another, allowing for each to be individually tuned. This leads to the formation of a general electromechanical model which presents a universal electronic blueprint for enhanced performances. Through this model, performance optimization and system miniaturization are enabled, with gauge factors (G) >108 for capsule diameters (D) ≈290 µm and produced at a record rate of >100 samples per second. When coalesced into quasi-2D planar networks, microcapsules form the basis of discrete, recyclable electronic smart skins with areal independent sensitives for muscular, breathing, pulse, and blood pressure measurements in real-time

Nanostructured DPA-MPC-DPA triblock copolymer gel for controlled drug release of ketoprofen and spironolactone

Objective: Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel, and elucidate underlying physiochemical properties. Methods Drug release profiles from DPA50-MPC250-DPA50 gel (pH 7.5), over 32 hours (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS), and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM), and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM). Key Findings DPA50-MPC250-DPA50 copolymer (15 % w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data was consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. Conclusions The DPA50-MPC250-DPA50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone. Keywords DPA-MPC-DPA, pH sensitive, Nanoparticles, Polymer gel, Drug delivery system, Controlled releas

Fluoxetine and thioridazine inhibitefflux and attenuate crystalline biofilm formation by Proteusmirabilis

Proteus mirabilis forms extensive crystalline biofilms on indwelling urethral catheters that block urineflow and lead to serious clinical complications. The Bcr/CflA efflux system has previously been identified as important for development of P. mirabilis crystalline biofilms, highlighting the potential for efflux pump inhibitors (EPIs) to control catheter blockage. Here we evaluate the potential for drugs already used in human medicine (fluoxetine and thioridazine) to act as EPIs in P. mirabilis, and control crystalline biofilm formation. Both fluoxetine and thioridazine inhibited efflux in P. mirabilis, and molecular modelling predicted both drugs interact strongly with the biofilm-associated Bcr/CflA efflux system.Both EPIs were also found to significantly reduce the rate of P. mirabilis crystalline biofilm formation on catheters, and increase the time taken for catheters to block. Swimming and swarming motilies inP. mirabilis were also significantly reduced by both EPIs. The impact of these drugs on catheter biofilm formation by other uropathogens (Escherichia coli, Pseudomonas aeruginosa) was also explored, and thioridazine was shown to also inhibit biofilm formation in these species. Therefore, repurposing of existing drugs with EPI activity could be a promising approach to control catheter blockage, or biofilmformation on other medical devices