Greg G. Qiao

Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers

With the recent emergence of reports on resistant Gram-negative ‘superbugs’, infections caused by multidrug-resistant (MDR) Gram-negative bacteria have been named as one of the most urgent global health threats due to the lack of effective and biocompatible drugs. Here, we show that a class of antimicrobial agents, termed ‘structurally nanoengineered antimicrobial peptide polymers’ (SNAPPs) exhibit sub-μM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy. Furthermore, we did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria.

Nucleic Acid Aptamer-Guided Cancer Therapeutics and Diagnostics: the Next Generation of Cancer Medicine

Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer-based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy.

From well defined star-microgels to highly ordered honeycomb films

Star-microgels were prepared in a two-step process known as the arm first approach by Atom Transfer Radical Polymerization (ATRP). Living linear poly(methyl methacrylate) (PMMA), with molecular weight (Mn) of 10000 and 20000, was reacted with ethylene glycol dimethacrylate (EGDMA) as crosslinker and varying amounts of methyl methacrylate (MMA) as spacer, under ATRP conditions, to produce star-microgels with Mn ranging from 0.3 × 106 to 1.0 × 106 and number of arms, n(arms) from 11 to 74. As Mn of the arm was increased, a decrease in molecular weight and in the number of arms in the microgel was observed. Star-microgels, with MMA spacer incorporated in the core, were found to have lower molecular weight and lower arm number. The microgels were used as precursors to form honeycomb films. The films were cast under conditions of high humidity which produces condensed water droplets which act as the template for a precipitating polymer. This is the first report of the use of well defined star-microgels to cast highly ordered porous films. It is shown that the pore diameters decrease with increasing number of PMMA arms and with increasing molecular weight of the star-microgel.

Cyclodextrin-based supramolecular assemblies and hydrogels: recent advances and future perspectives.

The application of cyclodextrin (CD)-based host-guest interactions towards the fabrication of functional supramolecular assemblies and hydrogels is of particular interest in the field of biomedicine. However, as of late they have found new applications as advanced functional materials (e.g., actuators and self-healing materials), which have renewed interest across a wide range of fields. Advanced supramolecular materials synthesized using this noncovalent interaction, exhibit specificity and reversibility, which can be used to impart reversible cross-linking, specific binding sites, and functionality. In this review, various functional CD-based supramolecular assemblies and hydrogels will be outlined with the focus on recent advances. In addition, an outlook will be provided on the direction of this rapidly developing field.

Recent Advances in Star Polymer Design: Degradability and the Potential for Drug Delivery

The use of polymers as drug delivery devices represents an exciting area of development in the biomedical industry. This paper briefly highlights some of the different types of macromolecules that have attracted attention as potential drug delivery devices, with a particular focus on the class of star polymers known as core cross-linked star (CCS) polymers. The ability to control the rate at which encapsulated molecules can be released is an important factor in the design of efficient drug delivery devices. In this regard, several different techniques to incorporate degradable functionality into CCS polymers are examined as a potential means of controlling release kinetics.

Folic Acid Conjugated Amino Acid-Based Star Polymers for Active Targeting of Cancer Cells

Amino acid-based core cross-linked star (CCS) polymers (poly(L-lysine)(arm)poly(L-cystine)(core)) with peripheral allyl functionalities were synthesized by sequential ring-opening polymerization (ROP) of amino acid N-carboxyanhydrides (NCAs) via the arm-first approach, using N-(trimethylsilyl)allylamine as the initiator. Subsequent functionalization with a poly(ethylene glycol) (PEG)-folic acid conjugate via thiol-ene click chemistry afforded poly(PEG-b-L-lysine)(arm)poly(L-cystine)(core) stars with outer PEG coronas decorated with folic acid targeting moieties. Similarly, a control was prepared without folic acid, using just PEG. A fluorophore was used to track both star polymers incubated with breast cancer cells (MDA-MB-231) in vitro. Confocal microscopy and flow cytometry revealed that the stars could be internalized into the cells, and higher cell internalization was observed when folic acid moieties were present. Cytotoxicity studies indicate that both stars are nontoxic to MDA-MB-231 cells at concentrations of up to 50 μg/mL. These results make this amino acid-based star polymer an attractive candidate in targeted drug delivery applications including chemotherapy.

Nitrile Imines: Matrix Isolation, IR Spectra, Structures, and Rearrangement to Carbodiimides

The structures and reactivities of nitrile imines are subjects of continuing debate. Several nitrile imines were generated photochemically or thermally and investigated by IR spectroscopy in Ar matrices at cryogenic temperatures (Ph-CNN-H 6, Ph-CNN-CH(3)17, Ph-CNN-SiMe(3)23, Ph-CNN-Ph 29, Ph(3)C-CNN-CPh(3)34, and the boryl-CNN-boryl derivative 39). The effect of substituents on the structures and IR absorptions of nitrile imines was investigated computationally at the B3LYP/6-31G* level. IR spectra were analyzed in terms of calculated anharmonic vibrational spectra and were generally in very good agreement with the calculated spectra. Infrared spectra were found to reflect the structures of nitrile imines accurately. Nitrile imines with IR absorptions above 2200 cm(-1) have essentially propargylic structures, possessing a CN triple bond (typically PhCNNSiMe(3)23, PhCNNPh 29, and boryl-CNN-boryl 39). Nitrile imines with IR absorptions below ca. 2200 cm(-1) are more likely to be allenic (e.g., HCNNH 1, PhCNNH 6, HCNNPh 43, PhCNNCH(3)17, and Ph(3)C-CNN-CPh(3)34). All nitrile imines isomerize to the corresponding carbodiimides both thermally and photochemically. Monosubstituted carbodiimides isomerize thermally to the corresponding cyanamides (e.g., Ph-N═C═N-H 5 → Ph-NH-CN 8), which are therefore the thermal end products for nitrile imines of the types RCNNH and HCNNR. This tautomerization is reversible under flash vacuum thermolysis conditions.

Chemical Cross-Linking Gelatin with Natural Phenolic Compounds as Studied by High-Resolution NMR Spectroscopy

Cross-linking gelatin with natural phenolic compound caffeic acid (CA) or tannic acid (TA) above pH 9 resulted in formation of insoluble hydrogels. The cross-linking reactivity was controlled by variation of pH, the concentration of the gelatin solution, or the amount of CA or TA used in the reaction. The cross-linking chemistry was studied by high-resolution NMR technique in both solution and solid state via investigation on small molecular model systems or using (13)C enriched caffeic acid (LCA) in the reaction with gelatin. Direct evidence was obtained to confirm the chemical reactions occurring between the phenolic reactive sites of the phenolic compounds and the amino groups in gelatin to form C-N covalent bonds as cross-linking linkages in gelatin matrix. The cross-linked network was homogeneous on a scale of 2-3 nm. The cross-linking resulted in a significant decrease in the molecular mobility of the hydrogels, while the modulus of the films remained at high values at high temperatures.

Solid–liquid separations with a temperature-responsive polymeric flocculant: Effect of temperature and molecular weight on polymer adsorption and deposition

The effects of temperature and molecular weight of the temperature-responsive polymer, poly(N-isopropylacrylamide) (PNIPAM) were investigated in the solid-liquid separation of silica and alumina mineral particles. Suspensions dosed with PNIPAM at 25 degrees C were stable and did not settle. When the temperature was raised above the polymer lower critical solution temperature (LCST) (>32 degrees C), the suspensions were found to have high settling rates, large particle aggregate sizes and high suspension shear yield stresses (tau(y)). The sediment bed solids volume fraction (phi(f)), of these suspensions was found to increase after a temperature decrease below the polymer LCST and was attributed to a decrease in the attractive particle-particle interactions as shown by a corresponding decrease in shear yield stress, with decreasing temperature. Settling rates were found to increase with molecular weight when suspensions were dosed at 25 degrees C and settled at 50 degrees C. Increasing polymer molecular weight resulted in increased molecular polymer adsorption at 25 degrees C. Greater initial adsorbed amounts of polymer on the surface produced more nucleation sites for deposition of additional polymer as the temperature was increased from 25 degrees C to above the LCST where polymer phase separation occurred. When the polymer was dosed at 50 degrees C, the rate of sedimentation was very low. Under these conditions, the polymer molecules associate with each other to form polymer aggregates of typically 1250 nm diameter. These colloidal polymer aggregates do not readily deposit on the particles surfaces such that mineral particle aggregation does not readily occur.

Beyond Traditional RAFT: Alternative Activation of Thiocarbonylthio Compounds for Controlled Polymerization

Recent developments in polymerization reactions utilizing thiocarbonylthio compounds have highlighted the surprising versatility of these unique molecules. The increasing popularity of reversible addition–fragmentation chain transfer (RAFT) radical polymerization as a means of producing well‐defined, ‘controlled’ synthetic polymers is largely due to its simplicity of implementation and the availability of a wide range of compatible reagents. However, novel modes of thiocarbonylthio activation can expand the technique beyond the traditional system (i.e., employing a free radical initiator) pushing the applicability and use of thiocarbonylthio compounds even further than previously assumed. The primary advances seen in recent years are a revival in the direct photoactivation of thiocarbonylthio compounds, their activation via photoredox catalysis, and their use in cationic polymerizations. These synthetic approaches and their implications for the synthesis of controlled polymers represent a significant advance in polymer science, with potentially unforeseen benefits and possibilities for further developments still ahead. This Research News aims to highlight key works in this area while also clarifying the differences and similarities of each system.