Daniel J. Coady

A Simple and Efficient Synthesis of Functionalized Cyclic Carbonate Monomers Using a Versatile Pentafluorophenyl Ester Intermediate

An improved two-step synthetic route to functionalized cyclic carbonate monomers that features a novel cyclic carbonate intermediate with an active pentafluorophenyl ester group (MTC-OPhF(5)) has been developed. The versatile pentafluorophenyl ester intermediate can be synthesized on the gram to kilogram scale in one high-yielding step and is easy to store and handle on the benchtop. The active pentafluorophenyl ester of MTC-OPhF(5) is amenable to further substitution with suitable nucleophiles such as alcohols and amines to generate functionalized cyclic carbonates in high yields. The substitution reaction is tolerant of a wide variety of functionalities, including various hydrophobic and hydrophilic groups, reactive functionalities (via thiol-ene click chemistry or alkyl halides), and protected acids, alcohols, thiols, and amines. In view of the ever-increasing need for biodegradable and biocompatible polymers, this new methodology provides a simple and versatile platform for the synthesis of new and innovative materials.

Recyclable, strong thermosets and organogels via paraformaldehyde condensation with diamines

Recyclable Thermoset Polymers The high mechanical strength and durability of thermoset polymers are exploited in applications such as composite materials, where they form the matrix surrounding carbon fibers. The thermally driven polymerization reaction is usually irreversible, so it is difficult to recycle the constituent monomers and to remove and repair portions of a composite part. García et al. (p. 732; see the Perspective by Long) now describe a family of polymers formed by condensation of paraformaldehyde with bisanilines that could form hard thermoset polymers or, when more oxygenated, produce self-healing gels. Strong acid digestion allowed recovery of the bisaniline monomers. A strong polymer formed by heating can be digested with strong acid to recover and recycle its bisaniline monomers. [Also see Perspective by Long] Nitrogen-based thermoset polymers have many industrial applications (for example, in composites), but are difficult to recycle or rework. We report a simple one-pot, low-temperature polycondensation between paraformaldehyde and 4,4ʹ-oxydianiline (ODA) that forms hemiaminal dynamic covalent networks (HDCNs), which can further cyclize at high temperatures, producing poly(hexahydrotriazine)s (PHTs). Both materials are strong thermosetting polymers, and the PHTs exhibited very high Young’s moduli (up to ~14.0 gigapascals and up to 20 gigapascals when reinforced with surface-treated carbon nanotubes), excellent solvent resistance, and resistance to environmental stress cracking. However, both HDCNs and PHTs could be digested at low pH (<2) to recover the bisaniline monomers. By simply using different diamine monomers, the HDCN- and PHT-forming reactions afford extremely versatile materials platforms. For example, when poly(ethylene glycol) (PEG) diamine monomers were used to form HDCNs, elastic organogels formed that exhibited self-healing properties.

Highly dynamic biodegradable micelles capable of lysing Gram-positive and Gram-negative bacterial membrane

The development of biodegradable antimicrobial polymers adds to the toolbox of attractive antimicrobial agents against antibiotic-resistant microbes. To this end, the potential of polycarbonate polymers as such materials were explored. A series of random polycarbonate polymers consisting of monomers MTC-OEt and MTC-CH(2)CH(3)Cl were designed and synthesized using metal-free organocatalytic ring-opening polymerization. Random polycarbonate polymers self-assembled in solution but appeared highly dynamic; such behaviors are desirable as ready disassembly of polymers at the microbial membrane facilitates membrane disruption. Their activities against clinically relevant Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (E.coli and Pseudomonas aeruginosa) revealed that the hydrophobic-hydrophilic composition balance in polymers are important to render antimicrobial potency. Scanning electron microscopy (SEM) studies indicated microbial cell surface damage after treatment with polymers, and confocal microscopy studies also showed entry of FITC-dextran dye in Escherichia coli as a result of membrane disruption. On the other hand, the polymers exhibited minimal toxicity against red blood cells in hemolysis tests. Therefore, these random polycarbonate polymers are promising antimicrobial agents against both Gram-positive and Gram-negative bacteria for various biomedical applications.

Broad-spectrum antimicrobial and biofilm-disrupting hydrogels: stereocomplex-driven supramolecular assemblies.

Fighting the resistance: biodegradable and injectable/moldable hydrogels with hierarchical nanostructures were made with broad-spectrum antimicrobial activities and biofilm-disruption capability. They demonstrate no cytotoxicity in vitro, and show excellent skin biocompatibility in animals. These hydrogels have great potential for clinical use in prevention and treatment of various multidrug-resistant infections.

Hydrophobic modification of low molecular weight polyethylenimine for improved gene transfection

Hydrophobic modification of low molecular weight (LMW) polyethylenimine (PEI) is known to increase gene transfection efficiency of LMW PEI. However, few studies have explored how the conjugated hydrophobic groups influence the properties of the modified LMW PEI mainly due to difficulties in obtaining well defined final product compositions and limitations in current chemical synthesis routes. The aim of this study was to modify LMW PEI (Mn 1.8 kDa, PEI-1.8) judiciously with different hydrophobic functional groups and to investigate how hydrophobicity, molecular structure and inclusion of hydrogen bonding properties in the conjugated side groups as well as the conjugation degree (number of primary amine groups of PEI-1.8 modified with hydrophobic groups) influence PEI-1.8 gene transfection efficiency. The modified polymers were characterized for DNA binding ability, particle size, zeta potential, in vitro gene transfection efficiency and cytotoxicity in SKOV-3 human ovarian cancer and HepG2 human liver carcinoma cell lines. The study shows that modified PEI-1.8 polymers are able to condense plasmid DNA into cationic nanoparticles, of sizes ~100 nm, whereas unmodified polymer/DNA complexes display larger particle sizes of 2 μm. Hydrophobic modification also increases the zeta potential of polymer/DNA complexes. Importantly, modified PEI-1.8 shows enhanced transfection efficiency over the unmodified counterpart. Higher transfection efficiency is obtained when PEI-1.8 is modified with shorter hydrophobic groups (MTC-ethyl) as opposed to longer ones (MTC-octyl and MTC-deodecyl). An aromatic structured functional group (MTC-benzyl) also enhances transfection efficiency more than an alkyl functional group (MTC-octyl). An added hydrogen-bonding urea group in the conjugated functional group (MTC-urea) does not enhance transfection efficiency over one without urea (MTC-benzyl). The study also demonstrates that modification degree greatly influences gene transfection, and ~100% substitution of primary amine groups leads to significantly lower gene transfection efficiency. These findings provide insights to modification of PEI for development of effective and non-cytotoxic non-viral vectors.

Rational design of biodegradable cationic polycarbonates for gene delivery

Polycarbonates provide an attractive option for use as gene delivery vectors owing to their biocompatibility and ease of incorporating functional moieties. In this study, we described an approach to synthesize cationic polymers with well-defined molecular weights and narrow polydispersities by an organocatalytic ring-opening polymerization of functional cyclic carbonates containing alkyl halide side chains, followed by a subsequent functionalization step with bis-tertiary amines designed to facilitate gene binding and endosomal escape. The cationic polycarbonate effectively condensed DNA at low N/P ratios, generating nanoparticles (83 to 124 nm in diameter) with positive zeta potentials (~27 mV). In addition, reporter gene expression efficiencies in HepG2, HEK293, MCF-7 and 4T1 cell lines were high even in the presence of serum. Importantly, the polycarbonate delivery agent demonstrated minimal cytotoxicity at the optimal N/P ratios determined to confer high gene expression efficiencies. Therefore, this biodegradable polymer is presented as a promising non-viral vector for gene delivery.

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.

Thermal Probe Maskless Lithography for 27.5 nm Half-Pitch Si Technology

Thermal scanning probe lithography is used for creating lithographic patterns with 27.5 nm half-pitch line density in a 50 nm thick high carbon content organic resist on a Si substrate. The as-written patterns in the poly phthaladehyde thermal resist layer have a depth of 8 nm, and they are transformed into high-aspect ratio binary patterns in the high carbon content resist using a SiO2 hard-mask layer with a thickness of merely 4 nm and a sequence of selective reactive ion etching steps. Using this process, a line-edge roughness after transfer of 2.7 nm (3σ) has been achieved. The patterns have also been transferred into 50 nm deep structures in the Si substrate with excellent conformal accuracy. The demonstrated process capabilities in terms of feature density and line-edge roughness are in accordance with todays requirements for maskless lithography, for example for the fabrication of extreme ultraviolet (EUV) masks.

Broad-spectrum antimicrobial supramolecular assemblies with distinctive size and shape

With the increased prevalence of antibiotic-resistant infections, there is an urgent need for innovative antimicrobial treatments. One such area being actively explored is the use of self-assembling cationic polymers. This relatively new class of materials was inspired by biologically pervasive cationic host defense peptides. The antimicrobial action of both the synthetic polymers and naturally occurring peptides is believed to be complemented by their three-dimensional structure. In an effort to evaluate shape effects on antimicrobial materials, triblock polymers were polymerized from an assembly directing terephthalamide-bisurea core. Simple changes to this core, such as the addition of a methylene spacer, served to direct self-assembly into distinct morphologies-spheres and rods. Computational modeling also demonstrated how subtle core changes could directly alter urea stacking motifs manifesting in unique multidirectional hydrogen-bond networks despite the vast majority of material consisting of poly(lactide) (interior block) and cationic polycarbonates (exterior block). Upon testing the spherical and rod-like morphologies for antimicrobial properties, it was found that both possessed broad-spectrum activity (Gram-negative and Gram-positive bacteria as well as fungi) with minimal hemolysis, although only the rod-like assemblies were effective against Candida albicans.

Delivery of Anticancer Drugs Using Polymeric Micelles Stabilized by Hydrogen‐Bonding Urea Groups

Polymeric micelles comprising a hydrogen-bonding core were formed from block copolymers with pendant urea groups and explored as drug delivery vehicles. The amphiphilic block copolymers were synthesized by organocatalytic ring opening polymerization (ROP) of urea-functionalized cyclic carbonates from a poly(ethylene glycol) macroinitiator. The urea functionality was incorporated because its ability to increase the hydrophobic cores affinity toward polar organic compounds through intermolecular hydrogen bonding. Doxorubicin (DOX), a lipophilic anticancer drug with hydrogen-bonding functionalities, was systematically incorporated into the micelles hydrophobic interior via hydrogen bonding to the functionalized monomers. Micelles employing urea groups were found to more efficiently interact with DOX thus allowing increased drug loading capacity while maintaining a desirable micellular size. More importantly, while DOX-loaded micelles were shown to kill HepG2 human liver carcinoma cell lines efficiently, all of the polymers were non-cytotoxic.