Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina.

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA).

Correction: Engineering microbial physiology with synthetic polymers: cationic polymers induce biofilm formation in and downregulate the expression of virulence genes.

[This corrects the article DOI: 10.1039/C7SC00615B.].

Structural Determinants of the Stability of Enzyme-Responsive Polyion Complex Nanoparticles Targeting 's Elastase.

Here, we report how the stability of polyion complex (PIC) particles containing 's elastase (LasB) degradable peptides and antimicrobial poly(ethylene imine) is significantly improved by careful design of the peptide component. Three LasB-degradable peptides are reported herein, all of them carrying the LasB-degradable sequence -GLA- and for which the number of anionic amino acids and cysteine units per peptide were systematically varied. Our results suggest that while net charge and potential to cross-link via disulfide bond formation do not have a predictable effect on the ability of LasB to degrade these peptides, a significant effect of these two parameters on particle preparation and stability is observed.

Poly(acryloyl hydrazide), a versatile scaffold for the preparation of functional polymers: synthesis and post-polymerisation modification.

Here we present the synthesis and post-polymerisation modification of poly(acryloyl hydrazide), a versatile scaffold for the preparation of functional polymers: poly(acryloyl hydrazide) was prepared from commercially available starting materials in a three step synthesis on a large scale, in good yields and high purity. Our synthetic approach included the synthesis of a Boc-protected acryloyl hydrazide, the preparation of polymers RAFT polymerisation and the deprotection of the corresponding Boc-protected poly(acryloyl hydrazide). Post-polymerisation modification of poly(acryloyl hydrazide) was then demonstrated using a range of conditions for both hydrophilic and hydrophobic aldehydes.

Different-Length Hydrazone Activated Polymers for Plasmid DNA Condensation and Cellular Transfection.

The recent advances in genetic engineering demand the development of conceptually new methods to prepare and identify efficient vectors for the intracellular delivery of different nucleotide payloads ranging from short single-stranded oligonucleotides to larger plasmid double-stranded circular DNAs. Although many challenges still have to be overcome, polymers hold great potential for intracellular nucleotide delivery and gene therapy. We here develop and apply the postpolymerization modification of polyhydrazide scaffolds, with different degree of polymerization, for the preparation of amphiphilic polymeric vehicles for the intracellular delivery of a circular plasmid DNA.

Lipopolysaccharide structure impacts the entry kinetics of bacterial outer membrane vesicles into host cells.

Outer membrane vesicles are nano-sized microvesicles shed from the outer membrane of Gram-negative bacteria and play important roles in immune priming and disease pathogenesis. However, our current mechanistic understanding of vesicle-host cell interactions is limited by a lack of methods to study the rapid kinetics of vesicle entry and cargo delivery to host cells. Here, we describe a highly sensitive method to study the kinetics of vesicle entry into host cells in real-time using a genetically encoded, vesicle-targeted probe.

Engineering microbial physiology with synthetic polymers: cationic polymers induce biofilm formation in and downregulate the expression of virulence genes.

Here we report the first application of non-bactericidal synthetic polymers to modulate the physiology of a bacterial pathogen. Poly(-[3-(dimethylamino)propyl] methacrylamide) () and poly(-(3-aminopropyl)methacrylamide) (), cationic polymers that bind to the surface of , the infectious agent causing cholera disease, can sequester the pathogen into clusters. Upon clustering, transitions to a sessile lifestyle, characterised by increased biofilm production and the repression of key virulence factors such as the cholera toxin (CTX).

Polymyxin B containing polyion complex (PIC) nanoparticles: Improving the antimicrobial activity by tailoring the degree of polymerisation of the inert component.

Here, we describe the preparation and characterisation of polyion complex (PIC) nanoparticles containing last resort antimicrobial polymyxin B (Pol-B). PIC nanoparticles were prepared with poly(styrene sulphonate) (PSS) as an inert component, across a range of degrees of polymerisation to evaluate the effect that multivalency of this electrolyte has on the stability and antimicrobial activity of these nanoparticles. Our results demonstrate that while nanoparticles prepared with longer polyelectrolytes are more stable under simulated physiological conditions, those prepared with shorter polyelectrolytes have a higher antimicrobial activity.

Polymers for binding of the gram-positive oral pathogen Streptococcus mutans.

Streptococcus mutans is the most significant pathogenic bacterium implicated in the formation of dental caries and, both directly and indirectly, has been associated with severe conditions such as multiple sclerosis, cerebrovascular and peripheral artery disease. Polymers able to selectively bind S. mutans and/or inhibit its adhesion to oral tissue in a non-lethal manner would offer possibilities for addressing pathogenicity without selecting for populations resistant against bactericidal agents.

Vesicles in Nature and the Laboratory: Elucidation of Their Biological Properties and Synthesis of Increasingly Complex Synthetic Vesicles.

The important role of vesicles in many aspects of cell function is well-recognized, but only recently have sophisticated imaging techniques begun to reveal their ubiquity in nature. While we further our understanding of the biological properties of vesicles and their physiological functions, increasingly elegant artificial vesicles are being developed for a wide range of technological applications and basic research. Herein, we examine the state of the art of biological and synthetic vesicles and place their biological features in the context of recent synthetic developments, thus providing a unique overview of these complex and rapidly developing fields.

Polyion complex (PIC) particles: Preparation and biomedical applications.

Oppositely charged polyions can self-assemble in solution to form colloidal polyion complex (PIC) particles. Such nanomaterials can be loaded with charged therapeutics such as DNA, drugs or probes for application as novel nanomedicines and chemical sensors to detect disease markers. A comprehensive discussion of the factors affecting PIC particle self-assembly and their response to physical and chemical stimuli in solution is described herein.

Enzyme-responsive polyion complex (PIC) nanoparticles for the targeted delivery of antimicrobial polymers.

Here we present new enzyme-responsive polyion complex (PIC) nanoparticles prepared from antimicrobial poly(ethylene imine) and an anionic enzyme-responsive peptide targeting 's elastase. The synthetic conditions used to prepare these nanomaterials allowed us to optimise particle size and charge, and their stability under physiological conditions. We demonstrate that these enzyme responsive PIC nanoparticles are selectively degraded in the presence of elastase without being affected by other endogenous elastases.

Dendrimer mediated clustering of bacteria: improved aggregation and evaluation of bacterial response and viability.

Here, we evaluate how cationic gallic acid-triethylene glycol (GATG) dendrimers interact with bacteria and their potential to develop new antimicrobials. We demonstrate that GATG dendrimers functionalised with primary amines in their periphery can induce the formation of clusters in Vibrio harveyi, an opportunistic marine pathogen, in a generation dependent manner. Moreover, these cationic GATG dendrimers demonstrate an improved ability to induce cluster formation when compared to poly(N-[3-(dimethylamino)propyl]methacrylamide) [p(DMAPMAm)], a cationic linear polymer previously shown to cluster bacteria.

In Situ Functionalized Polymers for siRNA Delivery.

A new method is reported herein for screening the biological activity of functional polymers across a consistent degree of polymerization and in situ, that is, under aqueous conditions and without purification/isolation of candidate polymers. In brief, the chemical functionality of a poly(acryloyl hydrazide) scaffold was activated under aqueous conditions using readily available aldehydes to obtain amphiphilic polymers. The transport activity of the resulting polymers can be evaluated in situ using model membranes and living cells without the need for tedious isolation and purification steps.

Fundamentals, achievements and challenges in the electrochemical sensing of pathogens.

Electrochemical sensors are powerful tools widely used in industrial, environmental and medical applications. The versatility of electrochemical methods allows for the investigation of chemical composition in real time and in situ. Electrochemical detection of specific biological molecules is a powerful means for detecting disease-related markers.

Cationic polymer mediated bacterial clustering: Cell-adhesive properties of homo- and copolymers.

New anti-infective materials are needed urgently as alternatives to conventional biocides. It has recently been established that polymer materials designed to bind to the surface of bacteria can induce the formation of cell clusters which enhance the expression of quorum sensing controlled phenotypes. These materials are relevant for anti-infective strategies as they have the potential to inhibit adhesion while at the same time modulating Quorum Sensing (QS) controlled virulence.

Bacteria-instructed synthesis of polymers for self-selective microbial binding and labelling.

The detection and inactivation of pathogenic strains of bacteria continues to be an important therapeutic goal. Hence, there is a need for materials that can bind selectively to specific microorganisms for diagnostic or anti-infective applications, but that can be formed from simple and inexpensive building blocks. Here, we exploit bacterial redox systems to induce a copper-mediated radical polymerization of synthetic monomers at cell surfaces, generating polymers in situ that bind strongly to the microorganisms that produced them.

Programmable polymer-DNA hydrogels with dual input and multiscale responses.

Combination switchable polymer-DNA hydrogels have been synthesized to respond to both a specific oligonucleotide recognition signal and a non-specific but biorelevant environmental trigger. The hydrogels exhibit rheological properties that can be modulated through interaction with complementary DNA strands and/or reduction. Furthermore, individual and combined oligonucleotide recognition and reduction responses allow control over pore sizes in the gel, enabling programmable release and transport of objects ranging from the nano- to micro-scale.

Programmed assembly of polymer-DNA conjugate nanoparticles with optical readout and sequence-specific activation of biorecognition.

Soft micellar nanoparticles can be prepared from DNA conjugates designed to assemble via base pairing such that strands containing a polymer corona and a cholesterol tail generate controlled supramolecular architecture. Functionalization of one DNA conjugate strand with a biorecognition ligand results in shielding of the ligand when in the micelle, while encoding of the DNA sequences with overhangs allows supramolecular unpacking by addition of a complementary strand and sequence-specific unshielding of the ligand. The molecular assembly/disassembly and 'on-off' switch of the recognition signal is visualized by FRET pair signalling, PAGE and a facile turbidimetric binding assay, allowing direct and amplified readout of nucleic acid sequence recognition.

Bacteria clustering by polymers induces the expression of quorum-sensing-controlled phenotypes.

Bacteria deploy a range of chemistries to regulate their behaviour and respond to their environment. Quorum sensing is one method by which bacteria use chemical reactions to modulate pre-infection behaviour such as surface attachment. Polymers that can interfere with bacterial adhesion or the chemical reactions used for quorum sensing are therefore a potential means to control bacterial population responses.

Nanoparticle transport in epithelial cells: pathway switching through bioconjugation.

The understanding and control of nanoparticle transport into and through cellular compartments is central to biomedical applications of nanotechnology. Here, it is shown that the transport pathway of 50 nm polystyrene nanoparticles decorated with vitamin B12 in epithelial cells is different compared to both soluble B12 ligand and unmodified nanoparticles, and this is not attributable to B12 recognition alone. Importantly, the study indicates that vitamin B12 -conjugated nanoparticles circumnavigate the lysosomal compartment, the destination of soluble vitamin B12 ligand.