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The limited application of traditional antioxidants to reducing elevated levels of reactive oxygen species (ROS) is potentially due to their lack of stability and biocompatibility when tested in a biological milieu. For instance, the poor biological antioxidant performance of small molecular nitroxides arises from their limited diffusion across cell membranes and their significant side effects when applied at high doses. Herein, we describe the use of nanostructured carriers to improve the antioxidant activity of a typical nitroxide derivative, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). Polymers with star-shaped structures were synthesised and were further conjugated to TEMPO moieties via amide linkages. The TEMPO-loaded stars have small hydrodynamic sizes (<20 nm), and are better tolerated by cells than free TEMPO in a breast cancer-fibroblast co-culture, a system exhibiting elevated ROS levels. At a well-tolerated concentration, the polymer with the highest TEMPO-loading capacity successfully downregulated ROS production in co-cultured cells (a significant decrease of up to 50% vs. basal ROS levels), which was accompanied by a specific reduction in superoxide anion generation in the mitochondria. In contrast, the equivalent concentration of free TEMPO did not achieve the same outcome. Further investigation showed that the TEMPO-conjugated star polymers can be recycled inside the cells, thus providing longer term scavenging activity. Cell association studies demonstrated that the polymers can be taken up by both cell types in the co-culture, and are found to co-locate with the mitochondria. Interestingly the stars exhibited preferential mitochodria targeting in the co-cultured cancer cells compared to accompanying fibroblasts. The data suggest the potential of TEMPO-conjugated star polymers to arrest oxidative stress for various applications in cancer therapy. [ABSTRACT FROM AUTHOR]

Inspired by the properties of the naturally occurring H2S donor, diallyl trisulfide (DATS, extracted from garlic), the biological behaviour of trisulfide-bearing PEG-conjugates was explored. Specifically, three conjugates comprising an mPEG tail and a cholesteryl head were investigated: conjugates bridged by a trisulfide linker (T), a disulfide linker (D) or a carbamate linker (C), and a fourth comprising two mPEG tails bridged by a trisulfide linker (P). H2S testing using both a fluorescent chemical probe in HEK293 cells and an amperometric sensor to monitor release in suspended cells, demonstrated the ability of the trisulfide conjugates, T and P, to release H2S in the presence of cellular thiols. Cytotoxicity and cytoprotective capacity on HEK293 cells showed that T was the best tolerated of the conjugates studied, and remarkably more so than D or C. Moreover, it was noted that application of T conferred a protective effect to the cells, effectively abolishing the toxicity associated with co-administered C. The interaction of conjugates and combinations thereof with the cell membrane of HEK cells, as well as ROS generation were also investigated. It was found that C caused significant membrane perturbation, correlating with high losses in cell viability and pronounced generation of ROS, especially in the mitochondria. T, however, did not disturb the membrane and was able to mitigate the generation of ROS, especially in the mitochondria. The interplay of the cholesteryl group and H2S donation for conferring cytoprotective effects was clearly demonstrated as P did not display tInspired by the properties of the naturally occurring H2S donor, diallyl trisulfide (DATS, extracted from garlic), the biological behaviour of trisulfide-bearing PEG-conjugates was explored. Specifically, three conjugates comprising an mPEG tail and a cholesteryl head were investigated: conjugates bridged by a trisulfide linker (T), a disulfide linker (D) or a carbamate linker (C), and a fourth comprising two mPEG tails bridged by a trisulfide linker (P). H2S testing using both a fluorescent chemical probe in HEK293 cells and an amperometric sensor to monitor release in suspended cells, demonstrated the ability of the trisulfide conjugates, T and P, to release H2S in the presence of cellular thiols. Cytotoxicity and cytoprotective capacity on HEK293 cells showed that T was the best tolerated of the conjugates studied, and remarkably more so than D or C. Moreover, it was noted that application of T conferred a protective effect to the cells, effectively abolishing the toxicity associated with co-administered C. The interaction of conjugates and combinations thereof with the cell membrane of HEK cells, as well as ROS generation were also investigated. It was found that C caused significant membrane perturbation, correlating with high losses in cell viability and pronounced generation of ROS, especially in the mitochondria. T, however, did not disturb the membrane and was able to mitigate the generation of ROS, especially in the mitochondria. The interplay of the cholesteryl group and H2S donation for conferring cytoprotective effects was clearly demonstrated as P did not display the same beneficial characteristics as T.he same beneficial characteristics as T. [ABSTRACT FROM AUTHOR]

Candida albicans (C. albicans) is a common fungal pathogen causing both localised and systemic infections. The majority of these infections are promoted by biofilm formation, providing a protective matrix for the embedded fungi thereby evading the host immune defence and promoting resistance against anti-mycotic agents. In this study, pH-responsive micellar systems based on poly-(ethylene glycol) ethyl ether methacrylate (PEGMA) and poly 2-(diethylamino) ethyl methacrylate (DEAEMA) block-copolymers of P(PEGMA-b-DEAEMA) were specifically developed and loaded with the antifungal itraconazole (ICZ) to defeat C. albicans biofilms. The P(PEGMA-b-DEAEMA) di-block polymer micelles demonstrated a particle size of 55 ± 6 nm and high ICZ loads (12.0 ± 0.5% w/w). Within the biofilm's acidic microenvironment, tertiary amines of the pH-sensitive DEAEMA block are protonated, altering their conformation and enhancing the release of the micellar contents. Encapsulation of ICZ within micelles significantly enhanced the activity against C. albicans biofilms, with a significant reduction in the biofilm biomass (>50%) and in the number of viable cells (2.4 Log reduction) achieved, compared with the non-encapsulated ICZ. Confocal microscopy revealed a high affinity and accumulation of the micelles in C. albicans biofilms as a result of their size and specific electrostatic interaction, hence their improved activity. P(PEGMA-b-DEAEMA) based pH-responsive micelles offer significant potential as antifungal carriers for controlling Candida infections. [ABSTRACT FROM AUTHOR]

This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-aminoethyl)-1,3-di-Boc-guanidine, 1-(3-aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL−1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 μg mL−1) than their imidazole and tertiary amine counterparts (HC10 of >217 μg mL−1). Oligomers showed the greatest selectivity for C. neoformans, with the C12- and 2C12-tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54–109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure–property relationships for antibacterial and antifungal materials. [ABSTRACT FROM AUTHOR]

We have investigated core-crosslinked star polymer nanoparticles designed with tunable release chemistries as potential nanocarriers for a photoactive Re(i) organometallic complex. The nanoparticles consisted of a brush poly(oligo-ethylene glycol)methyl ether acrylate (POEGA) corona and a cross-linked core of non-biodegradable N,N′-methylenebis(acrylamide) (MBAA) and either pentafluorophenyl acrylate (PFPA), 3-vinyl benzaldehyde (VBA) or diacetone acrylamide (DAAM). Each star was modified with an amine functionalized photodynamic agent (i.e. a rhenium(i) organometallic complex) resulting in the formation of either a stable amide bond (POEGA-star-PFPA), or hydrolytically labile aldimine (POEGA-star-VBA) or ketimine bonds (POEGA-star-DAAM). These materials revealed linker dependent photo- and cytotoxicity when tested in vitro against non-cancerous lung fibroblast MRC-5 cells and HeLa human cervical cancer cells: the toxicity results correlated with final intracellular Re concentrations. [ABSTRACT FROM AUTHOR]

Lipidated polymers, like their protein counterparts, may be useful in fields as diverse as biochemistry and drug delivery. As such, strategies for preparing lipidated polymers with defined molecular architecture are clearly warranted. Herein, we describe a broadly-applicable methodology for synthesizing such lipidated materials, and demonstrate how they can be applied to the preparation of nanostructured drug delivery vehicles. [ABSTRACT FROM AUTHOR]

A facile synthesis method of polymer diclofenac conjugates (PDCs) based on biocompatible polyurethane chemistry that provides a high drug loading and offers a high degree of control over diclofenac (DCF) release kinetics is described. DCF incorporating monomer was reacted with ethyl-l-lysine diisocyanate (ELDI) and different amounts of polyethylene glycol (PEG) in a one-step synthesis to yield polymers with pendent diclofenac distributed along the backbone. By adjusting the co-monomers feed ratio, the drug loading could be tailored accordingly to give DCF loading of up to 38 w/w%. The release rate could also be controlled easily by changing the amount of PEG in the backbone. Above 10 w/w% of PEG, the in vitro DCF release studies in physiological conditions showed an apparent zero-order profile without an initial burst effect for up to 120 days. The PDCs described may be suitable for long-term intra-articular (IA) delivery for the treatment of osteoarthritis (OA). [ABSTRACT FROM AUTHOR]

Garlic-derived polysulfides (e.g., diallyl trisulfide, DATS) act as potent donors of the cell-signalling mediator H2S when exposed to endogenous thiols. Inspired by this chemistry, we incorporated a trisulfide linkage into a conjugate comprising an mPEG tail and a cholesteryl head via thiol-mediated fragmentation chemistry. The synthesized conjugate releases H2S upon exposure to thiol even at intracellular levels. [ABSTRACT FROM AUTHOR]

Cu(0)-mediated polymerization was employed to synthesize a library of structurally varied cationic polymers and their application as antibacterial peptide mimics was assessed. Eight platform polymers were first synthesized with low degrees of polymerization (DP) using (2-Boc-amino)ethyl acrylate as the monomer and either ethyl α-bromoisobutyrate or dodecyl 2-bromoisobutyrate as the initiator (thus providing hydrocarbon chain termini of C2 or C12, respectively). A two-step modification strategy was then employed to generate the final sixteen-member polymer library. Specifically, an initial deprotection was employed to reveal the primary amine cationic polymers, followed by guanylation. The biocidal activity of these cationic polymers was assessed against various strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Polymers having a short segment of guanidine units and a C12 hydrophobic terminus were shown to provide the broadest antimicrobial activity against the panel of isolates studied, with MIC values approaching those for Gram-positive targeting antibacterial peptides: daptomycin and vancomycin. The C12-terminated guanidine functional polymers were assayed against human red blood cells, and a concomitant increase in haemolysis was observed with decreasing DP. Cytotoxicity was tested against HEK293 and HepG2 cells, with the lowest DP C12-terminated polymer exhibiting minimal toxicity over the concentrations examined, except at the highest concentration. Membrane disruption was identified as the most probable mechanism of bacteria cell killing, as elucidated by membrane permeability testing against E. coli. [ABSTRACT FROM AUTHOR]

We report a novel library of filomicelles in water comprising either polystyrene or various polymethacrylate cores prepared via temperature-induced morphological transformation (TIMT). The nanoworms demonstrate reproducibly uniform morphology while exhibiting a broad range of glass transition temperatures, high stability in buffer, and the ability to form smart reversible thermoresponsive gels. [ABSTRACT FROM AUTHOR]

Acid and disulfide biodegradable cross-linkers have been employed to generate microgel star polymers, using RAFT-polymer arms. RAFT end-groups were then exploited to attach functional compounds viaboth thiol–ene and thiol–pyridyl disulfide exchange reactions. [ABSTRACT FROM AUTHOR]

In this communication, we report on a new route to the functionalization of ATRP polymers exploiting their halide end-groups, which were converted successfully into reactive disulfide end-groups, using sodium methanethiosulfonate. The resultant disulfide-terminated polymers could then be reacted with different functional thiols to yield functional polymers exploiting either thiol/disulfide exchange chemistry or thiol/ene “click” reactions. [ABSTRACT FROM AUTHOR]

In this work, we combine reversible addition fragmentation transfer polymerization (RAFT) with cobalt catalytic chain transfer (CCT) to obtain ω-unsaturated polymers with relatively low polydispersity values. [ABSTRACT FROM AUTHOR]

Inspired by the properties of the naturally occurring H 2 S donor, diallyl trisulfide (DATS, extracted from garlic), the biological behaviour of trisulfide-bearing PEG-conjugates was explored. Specifically, three conjugates comprising an mPEG tail and a cholesteryl head were investigated: conjugates bridged by a trisulfide linker (T), a disulfide linker (D) or a carbamate linker (C), and a fourth comprising two mPEG tails bridged by a trisulfide linker (P). H 2 S testing using both a fluorescent chemical probe in HEK293 cells and an amperometric sensor to monitor release in suspended cells, demonstrated the ability of the trisulfide conjugates, T and P, to release H 2 S in the presence of cellular thiols. Cytotoxicity and cyto-protective capacity on HEK293 cells showed that T was the best tolerated of the conjugates studied, and remarkably more so than D or C. Moreover, it was noted that application of T conferred a protective effect to the cells, effectively abolishing the toxicity associated with co-administered C. The interaction of conjugates and combinations thereof with the cell membrane of HEK cells, as well as ROS generation were also investigated. It was found that C caused significant membrane perturbation, correlating with high losses in cell viability and pronounced generation of ROS, especially in the mitochondria. T, however, did not disturb the membrane and was able to mitigate the generation of ROS, especially in the mitochondria. The interplay of the cholesteryl group and H 2 S donation for conferring cytoprotective effects was clearly demonstrated as P did not display the same beneficial characteristics as T.

Garlic-derived polysulfides (e.g., diallyl trisulfide, DATS) act as potent donors of the cell-signalling mediator H 2 S when exposed to endogenous thiols. Inspired by this chemistry, we incorporated a trisulfide linkage into a conjugate comprising an mPEG tail and a cholesteryl head via thiol-mediated fragmentation chemistry. The synthesized conjugate releases H 2 S upon exposure to thiol even at intracellular levels.

To provide a molecular insight for guiding polymer coating in surface science and nanotechnology, here we examined the structures of brushed polyethylene glycol(bPEG)- and phosphorylcholine(bPC)-grafted iron oxide nanoparticles and analyzed their protein avoiding properties. We show bPC as an advantageous biomimetic alternative to PEG in rendering stealth nanostructures.