Precision Dosing of Antibiotics and Potentiators by Hypoxia-Responsive Nanoparticles for Overcoming Antibiotic Resistance in Gram-Negative Bacteria.

The stalling development of antibiotics, especially against intrinsically resistant Gram-negative pathogens associated with outer membranes, leads to an emerging antibiotic crisis across the globe. To breathe life into existing drugs, we herein report a hypoxia-responsive nanoparticle (NP) that encapsulates a hydrophobic antibiotic, rifampicin, and a cationic potentiator, polysulfonium. The simultaneous release of antibiotics and potentiators can be promoted and inhibited in response to the severity of bacterial-induced hypoxia, leading to antimicrobial dosing in a precision manner. Under the synergism of polysulfoniums with membrane-disruption capability, the NPs can intensively decrease the antibiotic dose by up to 66-95% in eliminating planktonic Gram-negative P. aeruginosa bacteria and achieve an 8-log reduction of bacteria in mature biofilms at rifampicin MIC. The NP formulation demonstrates that precision dosing of antibiotics and potentiators regulated by hypoxia provides a promising strategy to maximize efficacy and minimize toxicity in treating Gram-negative bacterial infection.

Predictive Value of N-Terminal Pro B-Type Natriuretic Peptide for Contrast-Induced Nephropathy Non-Recovery and Poor Outcomes Among Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Contrast-induced nephropathy (CIN) is a frequent complication in patients undergoing percutaneous coronary intervention (PCI). The degree of recovery of renal function from CIN may affect long-term prognosis. N-terminal pro B-type natriuretic peptide (NT-proBNP) is a simple but useful biomarker for predicting CIN. However, the predictive value of preprocedural NT-proBNP for CIN non-recovery and long-term outcomes in patients undergoing PCI remains unclear.Methods and Results: This study prospectively enrolled 550 patients with CIN after PCI between January 2012 and December 2018. CIN non-recovery was defined as persistent serum creatinine >25% or 0.5 mg/dL over baseline from 1 week to 12 months after PCI in patients who developed CIN. CIN non-recovery was observed in 40 (7.3%) patients. Receiver operating characteristic analysis indicated that the best NT-proBNP cut-off value for detecting CIN non-recovery was 876.1 pg/mL (area under the curve 0.768; 95% confidence interval [CI] 0.731-0.803). After adjusting for potential confounders, multivariable analysis indicated that NT-proBNP >876.1 pg/mL was an independent predictor of CIN non-recovery (odds ratio 1.94; 95% CI 1.03-3.75; P=0.0042). Kaplan-Meier curves showed higher rates of long-term mortality among patients with CIN non-recovery than those with CIN recovery (Chi-squared=14.183, log-rank P=0.0002). CONCLUSIONS: Preprocedural NT-proBNP was associated with CIN non-recovery among patients undergoing PCI. The optimal cut-off value for NT-proBNP to predict CIN non-recovery was 876.1 pg/mL.

Injectable Thermosensitive Iodine-Loaded Starch-g-poly(N-isopropylacrylamide) Hydrogel for Cancer Photothermal Therapy and Anti-Infection.

Although photothermal therapy (PTT) can effectively eliminate tumors, the normal tissues near tumors are inevitably damaged by heat and infected by bacteria, which greatly limits the therapeutic effect. In this work, an injectable thermosensitive hydrogel based on iodine-loaded starch-g-poly(N-isopropylacrylamide) (PNSI) is developed to overcome this problem. FTIR, 1 H NMR, and UV-vis spectra confirm the graft copolymerization of poly(N-isopropylacrylamide) with starch and the formation of "iodine-starch" complex. Transmission electron microscope images show PNSI polymer self-assembles into regular spherical nanogel with a size of ≈50 nm. The concentrated nanogel dispersion is a sol at room temperature and transforms to hydrogel at body temperature. Under NIR laser irradiation for 10 min, the ΔT of the nanogel dispersion approachs about 20 °C with excellent thermal stability and high cytotoxicity due to the photothermal effect of the "iodine-starch" complex. After intratumor injection, this injectable hydrogel efficiently inhibites the tumor growth under 808 nm laser irradiation. Furthermore, it can also suppress Staphylococcus aureus infection in the wound post-PTT due to the release of iodine, which promotes wound healing. Therefore, this injectable thermosensitive "iodine-starch" composite hydrogel with advantages of good biocompatible and easy preparation possesses potential application for tumor photothermal therapy and antibacterial infection.

Hyperbranched Polyesters Based on Indole- and Lignin-Derived Monomeric Aromatic Aldehydes as Effective Nonionic Antimicrobial Coatings with Excellent Biocompatibility.

This research aims to investigate nonionic hyperbranched polyesters (HBPs) derived from indole and lignin resources as new nontoxic antimicrobial coatings. Three nonionic HBPs with zero to two methoxy ether substituents on each benzene ring in the polymer backbones were synthesized by melt-polycondensation of three corresponding AB2 monomers. The molecular structures and thermal properties of the obtained HBPs were characterized by gel permeation chromatography, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry analyses. These HBPs were conveniently spin-coated on a silicon substrate, which exhibited significant antibacterial effect against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). The presence of methoxy substituents enhanced the antimicrobial effect, and the resulting polymers showed negligible leakage in water. Finally, the polymers with the methoxy functionality exhibited excellent biocompatibility according to the results of hemolysis and MTT assay, which may facilitate their biomedical applications.

Case Report: A Rare Syncope Case Caused by Abernethy II and a Review of the Literature.

Background: Abernethy malformation is an extremely rare anomaly of the splanchnic venous system, and only 2 cases that manifested as syncope had been reported previously. Case Presentation: A 24-year-old male had a 15-year history of jaundice and was in long-term use of hepatoprotective drugs. He was admitted for complaint of syncope. He underwent a series of examinations and cardiac ultrasound showed that his pulmonary artery pressure was elevated. Further imaging revealed the absence of intrahepatic portal veins. His blood ammonia was significantly increased. All signs and symptoms pointed to an Abernethy diagnosis. He was finally diagnosed as having Abernethy type II. He was discharged after 17 days of in-hospital treatment with sildenafil (50 mg/day) and ornithine aspartate (20 g/day). Conclusion: We now report this rare case of syncope that is caused by Abernethy malformation. As a typically pediatric disease, it was not identified in this patient until adulthood due to long-term treatment for jaundice and liver cirrhosis. Furthermore, we present a review of portosystemic shunts previously reported in the literature.

Broad-Spectrum Bactericidal Activity and Remarkable Selectivity of Main-Chain Sulfonium-Containing Polymers with Alternating Sequences.

Incorporation of cationic groups into polymers represents one of the most widely used strategies to prepare antibacterial materials. Sulfonium, as a typical cationic moiety, displays potent antibacterial efficacy in the form of small molecules, however, has long underperformed in polymeric systems. Herein, we developed a series of alternating polysulfoniums, where the hydrophobicity of each alternating unit can be accurately tuned by altering the monomer precursors. Excellent antibacterial activity against a broad spectrum of clinically relevant bacteria, including Methicillin-resistant Staphylococcus aureus, can be obtained in the optimal compositions with minimum bactericidal concentrations in the range of 1.25-10 µg/mL, as well as negligible hemolytic effect at polymer concentrations even up to 10000 µg/mL. Bacteria do not readily develop resistance to polysulfoniums due to the antibacterial action is possibly the membrane disrupting mechanism. This work demonstrates sulfonium-based polymers with well-defined sequences can function as a promising candidate to combat drug-resistant bacterial infection.

Main-Chain Sulfonium-Containing Homopolymers with Negligible Hemolytic Toxicity for Eradication of Bacterial and Fungal Biofilms.

Antimicrobials against planktonic cells and established biofilms at low doses are in increasing demand to tackle antibiotic-resistant biofilm infections. As a promising alternative to antibiotics, cationic polymers can effectively kill planktonic microbes but usually require high concentrations to eradicate the established biofilms. Herein, we developed a series of sulfonium-based homopolymers with cationic sulfoniums and alkane spacers in the main chain. These polysulfoniums presented effective activity against planktonic fungi (Candida albicans) and bacteria (Escherichia coli and Staphylococcus aureus) with minimum inhibition concentrations (MICs) of 0.5-32 µg/mL, and the optimal composition can provide an 80-90% reduction in biofilm mass and >99% killing of Candida albicans and Escherichia coli cells in 3-day mature biofilms at 2 × MIC as well as steadily low hemolytic toxicity. The influence of amphiphilicity and charge density of polysulfonium homopolymers on their antimicrobial activity against planktonic microbes and mature biofilms was investigated to provide insights for effective antimicrobial polymer design.

Proton Transfer Hydrogels: Versatility and Applications.

Proton transfer polymerization between thiol and epoxide groups is shown to be an adaptable and utilitarian method for the synthesis of hydrogels. For instance, the polymerization catalyst can be organic or inorganic, and the polymerization medium can be pure water, buffer solutions, or organic solvents. The gelation mechanism can be triggered at ambient conditions, at a physiological temperature of 37 °C, or through using light as an external stimulus. The ambient and photochemical methods both allow for nanoimprint lithography to produce freestanding patterned thick films. The required thiol- and epoxide-carrying precursors can be chosen from a long list of commercially available small molecular as well as polymeric materials. The water uptake, mechanical, and biodegradation properties of the gels can, therefore, be tuned through the choice of appropriate gelation precursors and polymerization conditions. Finally, the thio-ether groups of the cross-linked networks can be functionalized through a postgelation modification reaction to access sulfonium-based cationic structures. Such structural changes endow antibacterial properties to the networks. In their pristine form, however, the gels are biocompatible and nonadhesive, allowing cancer cells to grow in a cluster formation.

Large-area alignment of tungsten oxide nanowires over flat and patterned substrates for room-temperature gas sensing.

Alignment of nanowires over a large area of flat and patterned substrates is a prerequisite to use their collective properties in devices such as gas sensors. In this work, uniform single-crystalline ultrathin W18 O49 nanowires with diameters less than 2 nm and aspect ratios larger than 100 have been synthesized, and, despite their flexibility, assembled into thin films with high orientational order over a macroscopic area by the Langmuir-Blodgett technique. Alignment of the tungsten oxide nanowires was also possible on top of sensor substrates equipped with electrodes. Such sensor devices were found to exhibit outstanding sensitivity to H2 at room temperature.

Self-assembly of an interacting binary blend of diblock copolymers in thin films: a potential route to porous materials with reactive nanochannel chemistry.

Self-assembly of a binary mixture of poly(styrene)336-block-poly(4-vinyl pyridine)25 (PS336-b-P4VP25) and poly(ethylene glycol)113-block-poly(4-hydroxy styrene)25 (PEG113-b-P4HS25) is shown to give rise to a cylindrical morphology in thin films through pyridine/phenol-based hetero-complementary hydrogen bonding interactions between the P4VP and P4HS copolymer segments. Removal of the cylindrical phase (PEG-b-P4HS) allowed access to porous materials having a pore surface decorated with P4VP polymer blocks. These segments could be transformed into cationic polyelectrolytes through quaternization of the pyridine nitrogen atom. The resulting positively charged nanopore surface could recognize negatively charged gold nanoparticles through electrostatic interactions. This work, therefore, outlines the utility of the supramolecular AB/CD type of block copolymer towards preparation of ordered porous thin films carrying a chemically defined channel surface with a large number of reactive sites.

Enzyme-triggered cascade reactions and assembly of abiotic block copolymers into micellar nanostructures.

Catalytic action of an enzyme is shown to transform a non-assembling block copolymer, composed of a completely non-natural repeat unit structure, into a self-assembling polymer building block. To achieve this, poly(styrene) is combined with an enzyme-sensitive methacrylate-based polymer segment carrying carefully designed azobenzene side chains. Once exposed to the enzyme azoreductase, in the presence of coenzyme NADPH, the azobenzene linkages undergo a bond scission reaction. This triggers a spontaneous 1,6-self-elimination cascade process and transforms the initially hydrophobic methacrylate polymer segment into a hydrophilic hydroxyethyl methacrylate structure. This change in chemical polarity of one of the polymer blocks confers an amphiphilic character to the diblock copolymer and permits it to self-assemble into a micellar nanostructure in water.

Designing functionalizable hydrogels through thiol-epoxy coupling chemistry.

A novel and modular strategy has been developed for the preparation of reactive and functionalized hydrogels. In this strategy, thiol-epoxy coupling chemistry was employed for the formation of a hydrophilic network. The hydroxyl groups, generated during the coupling process, were then engaged in anchoring a fluorescent probe to the hydrogel scaffold.

Enzyme sensitive synthetic polymer micelles based on the azobenzene motif.

In this study, we investigate the potential of an artificial structural motif, azobenzene, in the preparation of enzyme sensitive polymeric nanostructures. For this purpose, an azobenzene linkage is established at the copolymer junction of an amphiphilic diblock copolymer. This polymer assembles into a micellar structure in water. Treatment with the enzyme azoreductase, in the presence of coenzyme NADPH, results in the cleavage of the azo-based copolymer junction and disruption of the micellar assembly. These results suggest that azobenezene is a useful non-natural structural motif for the preparation of enzyme responsive polymer nanoparticles. Due to the presence of azoreductase in the human intestine, such nanomaterials are anticipated to find applicability in the arena of colon-specific delivery systems.

Synthesis and self-assembly of dynamic covalent block copolymers: towards a general route to pore-functionalized membranes.

A diblock copolymer is designed to have incompatible blocks, unsymmetrical block lengths, and a reversible linkage. This copolymer self-assembles into nanostructured cylindrical morphology in thin films. Removal of the nanosized cylinders by breaking the reversible linkage then affords nanoporous membranes featuring a chemically reactive functionality in the pores.

Cononsolvency-induced micellization kinetics of pyrene end-labeled diblock copolymer of N-isopropylacrylamide and oligo(ethylene glycol) methyl ether methacrylate studied by stopped-flow light-scattering and fluorescence.

Cononsolvency-induced micellization kinetics of a pyrene end-labeled diblock copolymer of N-isopropylacrylamide and oligo(ethylene glycol) methyl ether methacrylate, Py-PNIPAM-b-POEGMA, was investigated in detail via a combination of stopped-flow light-scattering and fluorescence techniques. Upon a stopped-flow jump from pure methanol to proper methanol/water mixtures, scattered light intensity exhibited an initial increase and then stabilized out; whereas the time-dependence of monomer to excimer fluorescence intensity ratios (I E/I M) revealed an abrupt increase followed by a gradual decrease to plateau values. The dynamic traces of scattered intensity can be well fitted by double exponential functions, the obtained tau 1, scat and tau 2, scat can be ascribed to processes of forming quasi-equilibrium micelles and their relaxation into final equilibrium states, respectively. On the other hand, a triple exponential function was needed to fit the dynamic traces of I E/I M, leading to three characteristic relaxation times (tau 1, fluo, tau 2, fluo, and tau 3, fluo). It was found that the time scales of tau 1, scat and tau 2, scat obtained from stopped-flow light scattering were in general agreement with tau 2, fluo and tau 3, fluo obtained from stopped-flow fluorescence. Considering that excimer fluorescence is extremely sensitive to small aggregates, the newly detected fast process (tau 1, fluo) approximately 10 ms) by stopped-flow fluorescence should be ascribed to the early stage of micellization, i.e., the burst formation of small transient micelles, in which light scattering detection was still not sensitive enough. These small transient micelles fused and grew into quasi-equilibrium micelles, which then slowly relaxed into the final equilibrium state.

Facile preparation of well-defined AB2 Y-shaped miktoarm star polypeptide copolymer via the combination of ring-opening polymerization and click chemistry.

Well-defined AB2 Y-shaped miktoarm star polypeptide copolymer, PZLL-b-(PBLG)2, was synthesized via a combination of ring-opening polymerization (ROP) of alpha-amino acid N-carboxyanhydride (NCA) and click chemistry, where PZLL is poly(epsilon-benzyloxycarbonyl-L-lysine) and PBLG is poly(gamma-benzyl-L-glutamate). First, two types of primary-amine-containing initiators, N-aminoethyl 3,5-bis(propargyloxyl)-benzamide and 3-azidopropylamine, were synthesized and employed for the ROP of NCA, leading to the formation of dialkynyl-terminated PZLL and azide-terminated PBLG, dialkynyl-PZLL and PBLG-N3, respectively. The subsequent copper(I)-catalyzed cycloaddition reaction between dialkynyl-PZLL and slightly excess PBLG-N3 led to facile preparation of PZLL-b-(PBLG)2 Y-shaped miktoarm star polypeptide copolymer. The excess PBLG-N3 was scavenged off by reacting with alkynyl-functionalized Wang resin. The obtained Y-shaped miktoarm star polypeptide copolymer was characterized by gel permeation chromatograph (GPC), Fourier transform-infrared spectroscopy (FT-IR), and (1)H NMR. Moreover, after the hydrolysis of protecting benzyl and benzyloxycarbonyl groups of PZLL-b-(PBLG)2, water-soluble pH-responsive Y-shaped miktoarm star polypeptide copolymer, PLL-b-(PLGA)2, was obtained, where PLL is poly(L-lysine) and PLGA is poly(L-glutamic acid). It can self-assemble into PLGA-core micelles at acidic pH and PLL-core micelles at alkaline pH, accompanied with the coil-to-helix transition of PLGA and PLL sequences, respectively. The spontaneous pH-responsive supramolecular assembly of PLL-b-(PLGA)2 miktoarm star polypeptide copolymer has been investigated via a combination of (1)H NMR, laser light scattering (LLS), transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy.

"Schizophrenic" micellization associated with coil-to-helix transitions based on polypeptide hybrid double hydrophilic rod-coil diblock copolymer.

A polypeptide hybrid double hydrophilic diblock copolymer (DHBC), poly( N-isopropylacrylamide)- b-poly( l-glutamic acid) (PNIPAM- b-PLGA), was synthesized via the ring-opening polymerization of gamma-benzyl- l-glutamate N-carboxyanhydride (BLG-NCA) using monoamino-terminated PNIPAM as the macroinitiator, followed by deprotection of benzyl groups under alkaline conditions. Containing a thermoresponsive PNIPAM block and a pH-responsive PLGA block, the obtained polypeptide hybrid diblock copolymer molecularly dissolves in aqueous solution at alkaline pH and room temperature but supramolecularly self-assembles into PNIPAM-core micelles at alkaline pH and elevated temperatures and PLGA-core micelles at acidic pH and room temperature accompanied with coil-to-helix transition of the PLGA sequence. The pH- and thermoresponsive "schizophrenic" micellization behavior of PNIPAM- b-PLGA diblock copolymer has been investigated by (1)H NMR, optical transmittance, fluorescence probe measurement, transmission electron microscopy (TEM), dynamic and static laser light scattering (LLS), and circular dichroism (CD) spectroscopy. Moreover, the micellization process was investigated employing stopped-flow light scattering technique. The pH-induced micelle growth of PNIPAM- b-PLGA in aqueous solution exhibits drastically different kinetics compared to that of conventional pH-responsive DHBCs, probably due to the stabilization effects exerted by the formed alpha-helix secondary structures within the PLGA core at low pH. Exhibiting "schizophrenic" micellization, the polypeptide sequence of PNIPAM- b-PLGA can either locate within micelle cores or stabilizing coronas. The incorporation of polypeptide block into DHBCs can endow them with structural versatility, tunable spatial arrangement of chain segments within self-assembled nanostructures, and broader applications in the field of biomedicines.

Cononsolvency-induced micellization of pyrene end-labeled diblock copolymers of N-isopropylacrylamide and oligo(ethylene glycol) methyl ether methacrylate.

Pyrene end-labeled double hydrophilic diblock copolymers, poly(N-isopropylacrylamide)-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (Py-PNIPAM-b-POEGMA), were synthesized via consecutive reversible addition-fragmentation chain transfer polymerization using a pyrene-containing dithioester as the chain transfer agent. These diblock copolymers molecularly dissolve in pure methanol and water, but form well-defined and nearly monodisperse PNIPAM-core micelles in an appropriate mixture of them due to the cononsolvency of PNIPAM block. 1H NMR, laser light scattering, fluorescence spectroscopy, and transmission electron microscopy were employed to characterize the cononsolvency-induced PNIPAM-core micelles. When the volume fraction of water, phi water, in the methanol/water mixture is in the range of 0.5-0.8, the sizes of micelles are in the range of 20-30 nm in radius for Py-PNIPAM50-b- POEGMA18. At phi water = 0.5, the formed micelles possess the highest overall micelle density and the largest molar mass. The effects of varying the block lengths of Py-PNIPAM-b-POEGMA diblock copolymers on the structural parameters of PNIPAM-core micelles have also been explored. Although we can observe the immediate appearance of bluish tinge upon mixing the diblock copolymer solution in methanol with equal volume of water (phi water = 0.5), which is characteristic of the formation of micellar aggregates, the whole micellization process apparently takes a relatively long time to complete, as revealed by monitoring the time dependence of fluorescence emission spectra. The excimer/monomer fluorescence intensity ratios, IE/IM, continuously decrease with time and then reach a plateau value after approximately 20 min. The decrease of IE/IM after the initial formation of pseudo-equilibrium micelles should be ascribed to the structural rearrangement and further packing of PNIPAM segments within the micelle core, restricting the mobility of pyrene end groups and decreasing the probability of contact between them. Compared to the conventional cosolvent approach employed for the micellization of block copolymers in selective solvents, the reported cononsolvency-induced unimer-micelle-unimer transition of Py-PNIPAM-b-POEGMA in methanol/water mixtures has been unprecedented.

Synthesis and "schizophrenic" micellization of double hydrophilic AB4 miktoarm star and AB diblock copolymers: structure and kinetics of micellization.

Poly(N-isopropylacrylamide) (PNIPAM)-based tetrafunctional atom transfer radical polymerization (ATRP) macroinitiator (1b) was synthesized via addition reaction of mono-amino-terminated PNIPAM (1a) with glycidol, followed by esterification with excess 2-bromoisobutyryl bromide. Well-defined double hydrophilic miktoarm AB4 star copolymer, PNIPAM-b-(PDEA)4, was then synthesized by polymerizing 2-(diethylamino)ethyl methacrylate (DEA) via ATRP in 2-propanol at 45 degrees C using 1b, where PDEA was poly(2-(diethylamino)ethyl methacrylate). For comparison, PNIPAM-b-PDEA linear diblock copolymer with comparable molecular weight and composition to that of PNIPAM-b-(PDEA)4 was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization. The pH- and thermoresponsive "schizophrenic" micellization behavior of the obtained PNIPAM65-b-(PDEA63)4 miktoarm star and PNIPAM70-b-PDEA260 linear diblock copolymers were investigated by 1H NMR and laser light scattering (LLS). In acidic solution and elevated temperatures, PNIPAM-core micelles were formed; whereas at slightly alkaline conditions and room temperature, structurally inverted PDEA-core micelles were formed. The size of the PDEA-core micelles of PNIPAM65-b-(PDEA63)4 is much smaller than that of PNIPAM70-b-PDEA260. Furthermore, the pH-induced micellization kinetics of the AB4 miktoarm star and AB block copolymers were investigated by the stopped-flow light scattering technique upon a pH jump from 4 to 10. Typical kinetic traces for the micellization of both types of copolymers can be well fitted with double-exponential functions, yielding a fast (tau1) and a slow (tau2) relaxation processes. tau1 for both copolymers decreased with increasing polymer concentration. tau2 was independent of polymer concentration for PNIPAM65-b-(PDEA63)4, whereas it decreased with increasing polymer concentration for PNIPAM70-b-PDEA260. The chain architectural effects on the micellization properties and the underlying mechanisms were discussed in detail.