Julian M. W. Chan

Antimicrobial hydrogels: A new weapon in the arsenal against multidrug-resistant infections☆

The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Treatment with conventional antibiotics often leads to resistance development as the majority of these antibiotics act on intracellular targets, leaving the bacterial morphology intact. Thus, they are highly prone to develop resistance through mutation. Much effort has been made to develop macromolecular antimicrobial agents that are less susceptible to resistance as they function by microbial membrane disruption. Antimicrobial hydrogels constitute an important class of macromolecular antimicrobial agents, which have been shown to be effective in preventing and treating multidrug-resistant infections. Advances in synthetic chemistry have made it possible to tailor molecular structure and functionality to impart broad-spectrum antimicrobial activity as well as predictable mechanical and rheological properties. This has significantly broadened the scope of potential applications that range from medical device and implant coating, sterilization, wound dressing, to antimicrobial creams for the prevention and treatment of multidrug-resistant infections. In this review, advances in both chemically and physically cross-linked natural and synthetic hydrogels possessing intrinsic antimicrobial properties or loaded with antibiotics, antimicrobial polymers/peptides and metal nanoparticles are highlighted. Relationships between physicochemical properties and antimicrobial activity/selectivity, and possible antimicrobial mechanisms of the hydrogels are discussed. Approaches to mitigating toxicity of metal nanoparticles that are encapsulated in hydrogels are reviewed. In addition, challenges and future perspectives in the development of safe and effective antimicrobial hydrogel systems especially involving co-delivery of antimicrobial polymers/peptides and conventional antimicrobial agents for eventual clinical applications are presented.

Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles

Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed.

Broad-Spectrum Antimicrobial Polycarbonate Hydrogels with Fast Degradability

In this study, a new family of broad-spectrum antimicrobial polycarbonate hydrogels has been successfully synthesized and characterized. Tertiary amine-containing eight-membered monofunctional and difunctional cyclic carbonates were synthesized, and chemically cross-linked polycarbonate hydrogels were obtained by copolymerizing these monomers with a poly(ethylene glycol)-based bifunctional initiator via organocatalyzed ring-opening polymerization using 1,8-diazabicyclo[5.4.0]undec-7-ene catalyst. The gels were quaternized using methyl iodide to confer antimicrobial properties. Stable hydrogels were obtained only when the bifunctional monomer concentration was equal to or higher than 12 mol %. In vitro antimicrobial studies revealed that all quaternized hydrogels exhibited broad-spectrum antimicrobial activity against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus), while the antimicrobial activity of the nonquaternized hydrogels was negligible. Moreover, the gels showed fast degradation at room temperature (4-6 days), which makes them ideal candidates for wound healing and implantable biomaterials.

Organic Acid-Catalyzed Polyurethane Formation via a Dual-Activated Mechanism: Unexpected Preference of N-Activation over O-Activation of Isocyanates

A systematic study of acid organocatalysts for the polyaddition of poly(ethylene glycol) to hexamethylene diisocyanate in solution has been performed. Among organic acids evaluated, sulfonic acids were found the most effective for urethane formations even when compared with conventional tin-based catalysts (dibutyltin dilaurate) or 1,8-diazabicyclo[5.4.0]undec-7-ene. In comparison, phosphonic and carboxylic acids showed considerably lower catalytic activities. Furthermore, sulfonic acids gave polyurethanes with higher molecular weights than was observed using traditional catalyst systems. Molecular modeling was conducted to provide mechanistic insight and supported a dual activation mechanism, whereby ternary adducts form in the presence of acid and engender both electrophilic isocyanate activation and nucleophilic alcohol activation through hydrogen bonding. Such a mechanism suggests catalytic activity is a function of not only acid strength but also inherent conjugate base electron density.

Homogeneous isocyanate- and catalyst-free synthesis of polyurethanes in aqueous media

We report an efficient and environmentally-friendly method of synthesizing polyurethanes in aqueous solution via an isocyanate- and catalyst-free polymerization process. Five different polyurethanes were synthesized by first activating 1,6-hexanediol and poly(ethylene glycol) with bis(pentafluorophenyl)carbonate, and then polycondensing various ratios of the 1,6-hexanediol/poly(ethylene glycol)-derived activated carbonates with JEFFAMINE. The polymerization process was confirmed by FTIR spectroscopy, 1H NMR spectroscopy, and gel permeation chromatography (GPC). The melting temperature was linearly dependent on the 1,6-hexanediol/poly(ethylene glycol) ratio, increasing with greater poly(ethylene glycol) content, as confirmed by differential scanning calorimetry (DSC). Similarly, the degree of crystallinity was also directly proportional to the poly(ethylene glycol) content.

Highly tunable polyurethanes: organocatalyzed polyaddition and subsequent post-polymerization modification of pentafluorophenyl ester sidechains

A facile method for the synthesis of high molecular weight functionalized polyurethanes from a novel pentafluorophenyl ester-containing diol precursor is described. Specifically, polyurethanes containing the activated ester sidechains were synthesized via triflic acid-catalyzed polyaddition of the above diol with diisocyanates. This was followed by quantitative postpolymerization modification of the sidechains with various primary amines. This method represents an efficient and modular synthetic strategy for the preparation of functionalized polyurethanes.

Thermoresponsive Random Poly(ether urethanes) with Tailorable LCSTs for Anticancer Drug Delivery

A new class of thermoresponsive random polyurethanes is successfully synthesized and characterized. Poly(ethylene glycol) diol (Mn = 1500 Da) and 2,2-dimethylolpropionic acid are reacted with isophorone diisocyanate in the presence of methane sulfonic acid catalyst. It is found that these polyurethanes are thermoresponsive in aqueous media and manifest a lower critical solution temperature (LCST) that can be easily tuned from 30 °C to 70 °C by increasing the poly(ethylene glycol) content. Their sharp LCST transitions make these random polyurethanes ideal candidates for stimuli-responsive drug delivery applications. To that end, the ability of these systems to efficiently sequester doxorubicin (up to 36 wt%) by means of a sonication/dialysis method is successfully demonstrated. Additionally, it is also demonstrated that accelerated doxorubicin release kinetics from the nanoparticles can be attained above the LCST.

Chemically modifiable N-heterocycle-functionalized polycarbonates as a platform for diverse smart biomimetic nanomaterials

A series of functional aliphatic polycarbonates bearing pendant N-heterocycles has been synthesized using a facile and modular synthetic strategy. This allows rapid access to a diverse range of biomimetic nanostructured materials that show promise as non-fouling polyzwitterions, host-defense peptide mimics, and potential drug/gene-delivery vectors, all starting from a common precursor. Preliminary biological data indicate promising non-fouling properties, antimicrobial activity, and negligible toxicity in human cell lines.

Polyurethane-coated silica particles with broad-spectrum antibacterial properties

Antimicrobial polymer-coated silica particles were synthesized using a “grafting to” approach. A number of polyurethanes (PU) and poly(ethylene glycol)-containing polyurethanes (PU-PEG) with and without free isocyanate end groups were synthesized by metal-free organocatalytic polymerization of isophorone diisocyanate and N-methyldiethanolamine in the absence or presence of PEG diol using 1,8-diazabicyclo[5.4.0]undec-7-ene as the catalyst, followed by covalent grafting onto primary amine, propyl chloride or benzyl chloride-functionalized silica particles via both surface-to-end-group (primary amine to isocyanate) and surface-to-backbone (propyl chloride or benzyl chloride to tertiary amine in PU and PU-PEG backbones, which generated quaternary ammoniums) attachment modes, resulting in various structures of the polymer-grafted surface. The free tertiary amine groups in the polymer coatings were quaternized using benzyl bromide or methyl iodide to impart antibacterial function. The samples were characterized by X-ray photoelectron spectroscopy (XPS), while their antibacterial efficacies and killing kinetics against Gram-positive S. aureus and Gram-negative E. coli were investigated. XPS spectra showed that the attachment mode on different types of surface-functionalized silica particles resulted in various degrees of polymer conjugation and subsequently led to varying antibacterial efficacies. The surface-to-end-group attachment mode after post-quaternization, in particular, produced PU-PEG-coated silica particles with excellent antibacterial potency against S. aureus and E. coli at a low particle concentration of 10 and 40 mg mL−1, respectively. By using the same batch of particles in repeated applications, it was found that the antibacterial effectiveness was maintained, and the surface-grafted polymer was stable. Overall, these polymer-coated silica particles have good potential for practical antibacterial applications.

Overcoming Multidrug Resistance in Microbials Using Nanostructures Self-Assembled from Cationic Bent-Core Oligomers

Novel cationic molecules based on rigid terephthalamide-bisurea cores flanked by imidazolium moieties are described. In aqueous media, these compounds self-assemble into supramolecular nanostructures with distinct morphologies. The compound with optimal hydrophilic/hydrophobic balance displays potent antimicrobial activity and high selectivity towards clinically-isolated MRSA without inducing drug-resistance. These self-assembled cationic antimicrobial nanostructures show promise for the prevention and treatment of multidrug-resistant infections.