“Clicked” into place: Densely grafted poly(γ‐propargyl‐L‐glutamate)‐g‐poly(ethylene glycol) polypeptides have been synthesized by combining ring‐opening polymerization of N‐carboxyanhydrides with ...click chemistry. Various lengths of poly(ethylene glycol) (PEG) side chains (750 g mol−1 to 5000 g mol−1) were attached to a rigid α‐helical poly(γ‐propargyl‐L‐glutamate); extremely high grafting efficiencies of over 96 % were achieved.
Abstract Intravascular catheter-associated infections (CAIs), which are normally induced by microbial adhesion and subsequent biofilm formation, are a major cause of morbidity and mortality. ...Therefore, strategies to prevent CAIs are in great demand. In this study, a series of diblock copolymers of PEG and cationic polycarbonate with various compositions were synthesized by metal-free organocatalytic ring-opening polymerization, and coated onto silicone rubber (a commonly used catheter material) at different concentrations via a reactive polydopamine coating. Static contact angle and X-ray photoelectron spectroscopy measurements proved the successful coating, and quartz crystal microbalance results showed that the coating thickness increased as polymer concentration increased. Methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates – leading causes of intravascular CAIs – were employed to evaluate the antibacterial and antifouling activities of the polymer coatings. Polymer coatings with a hydrophobic component effectively killed planktonic MSSA and MRSA in solution and prevented their fouling on silicone rubber surface. Live/dead cell staining experiments revealed that polymer coatings with the optimal polymer composition possessed significantly higher antifouling activity than PEG coating. In addition, scanning electron microscopic studies showed that the polymer coating inhibited S. aureus biofilm formation over a period of 7 days. Furthermore, the polymer coating caused no significant hemolysis, and there was no blood protein adsorption or platelet adhesion observed. Therefore, PEG- b -cationic polycarbonates with optimal compositions are effective antifouling and antibacterial coatings for the prevention of intravascular CAIs.
Microbial colonization and biofilm formation is the leading cause of contact lens-related keratitis. Treatment of the condition remains a challenge because of the need for prolonged therapeutic ...course and high doses of antimicrobial agents especially for biofilm eradication. The development of strategies to prepare nonfouling contact lens surfaces is a more practical way to ensure users’ safety and relieve the excessive public healthcare burden. In this study, we report a series of polymers that were modified to introduce functionality designed to facilitate coating adhesion, antimicrobial and antifouling properties. Cyclic carbonate monomers having different functional groups including adhesive catechol, antifouling poly(ethylene glycol) (PEG), and hydrophobic urea/ethyl were conjugated onto branched poly(ethylenimine) (bPEI, 25 kDa) at various degrees in a facile and well-controlled manner using a simple one step, atom economical approach. Immersion of contact lenses into an aqueous solution of the catechol-functionalized polymers at room temperature resulted in robust and stable coating on the lens surfaces, which survived the harsh condition of autoclaving and remained on the surface for a typical device application lifetime (7 days). The deposition of the polymer was unambiguously confirmed by static contact angle measurement and X-ray photoelectron spectroscopy (XPS). Polymer coating did not change light transmission significantly. Combinatorial optimization demonstrated that lenses coated with bPEI functionalized with catechol, PEG (5 kDa) and urea groups at 1:12:3:23 molar ratio for 18 h provided the highest antifouling effect against four types of keratitis-causing pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Fusarium solani, after 7 days of incubation. The polymer coating also inhibited protein adsorption onto the contact lens surfaces after exposure to bovine serum albumin solution for up to 24 h, owing to the flexible and large PEG constituent. Notably, all the polymer coatings used in this study were biocompatible, achieving ≥90% cell viability following direct contact with human corneal epithelial cells for 24 h. Hence, these polymer coatings are envisaged to be promising for the prevention of contact lens-related keratitis.
Abstract 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.
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► Recent advances in synthetic membrane-active macromolecule antimicrobials. ► Structural parameters that govern activity and selectivity of macromolecules. ► Effects of ...nanostructure, helical conformation, and hyperbrancing. ► Outlook on the development of safe and effective macromolecular antimicrobials.
Synthetic macromolecular antimicrobials are a highly promising class of therapeutics with immense potential for combating multidrug resistant microbes. In contrast to conventional small molecule antibiotics, macromolecular antimicrobial agents mediate physical disruption of microbial cell membranes, thereby reducing the likelihood of pathogens developing resistance. This review highlights recent advances in the development of synthetic membrane-active macromolecules with focus on peptides and polymers that adopt well-defined nanostructures or conformations (e.g. secondary helical structures, self-assembled nanoparticles, and hyperbranched structures). An overview of proposed antimicrobial mechanisms, followed by a description of structural parameters which govern selectivity of macromolecular agents for microbial cells over mammalian cells is provided. Pertinent examples of well-defined nanostructure-based macromolecular antimicrobial agents are discussed. Moreover, challenges and future perspectives in the development of safe and effective macromolecular antimicrobial agents for eventual clinical applications are presented.
Biodegradable antimicrobial polymers are a promising solution for combating drug resistant microbes. When designing these materials, the balance between charge and hydrophobicity significantly ...affects the antimicrobial activity and selectivity toward microbes over mammalian cells. Furthermore, where the charge and hydrophobicity is located on the molecules has also proven to be significant. A series of antimicrobial homopolymer polycarbonates were synthesized, where the hydrophobic/hydrophilic balance was controlled by varying the spacer between the charged quaternary ammonium moiety and the polymer backbone (a “same-centered” structure where the hydrophobic moiety is directly attached to the charged moiety). These homopolymers were active against all microbes tested but depending on the spacer length some hemolytic activity was observed. To reduce the polymer hemolytic activity we systematically varied the polymer composition by copolymerizing the different monomers used in the “same center” homopolymers. By maintaining charge on each repeat unit but copolymerizing monomers having varied hydrophobic side chain lengths, polymers with high activity and selectivity were achieved. In addition, these macromolecules act via a membrane disruption mechanism, making them less likely to induce resistance.
One of the major obstacles that delay the clinical translation of polymeric micelle drug delivery systems is whether these self-assembled micelles can retain their integrity in blood following ...intravenous (IV) injection. The objective of this study was to evaluate the impact of core functionalization on the thermodynamic and kinetic stability of polymeric micelles. The combination of ring-opening polymerization of N-carboxyanhydride (NCA) with highly efficient “click” coupling has enabled easy and quick access to a family of poly(ethylene glycol)-block-poly(γ-R-glutamate)s with exactly the same block lengths, for which the substituent “R” is tuned. The structures of these copolymers were carefully characterized by 1H NMR, FT-IR, and GPC. When pyrene is used as the fluorescence probe, the critical micelle concentrations (CMCs) of these polymers were found to be in the range of 10–7–10–6 M, which indicates good thermodynamic stability for the self-assembled micelles. The incorporation of polar side groups in the micelle core leads to high CMC values; however, micelles prepared from these copolymers are kinetically more stable in the presence of serum and upon SDS disturbance. It was also observed that these polymers could effectively encapsulate paclitaxel (PTX) as a model anticancer drug, and the micelles possessing better kinetic stability showed better suppression of the initial “burst” release and exhibited more sustained release of PTX. These PTX-loaded micelles exerted comparable cytotoxicity against HeLa cells as the clinically approved Cremophor PTX formulation, while the block copolymers showed much lower toxicity compared to the cremophor–ethanol mixture. The present work demonstrated that the PEG-b-PPLG can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block.
Fighting the resistance: Biodegradable and injectable/moldable hydrogels with hierarchical nanostructures (see picture) 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.
Direct-write 3D printing enables the fabrication of three-dimensional objects via the extrusion from a nozzle. Stimuli responsive materials that shear-thin are well-suited as inks for these 3D ...printing systems. Poly(isopropyl glycidyl ether)-block-poly(ethylene oxide)-block-poly(isopropyl glycidyl ether) ABA triblock copolymers were synthesized using controlled ring-opening polymerization to afford dual stimuli-responsive polymers that respond to both shear forces and temperature. These polymers were demonstrated to form hydrogels in water. The gels were observed to be thermoreversibledriven by the lower critical solution temperature of the poly(isopropyl glycidyl ether) block which helps facilitate loading of the ink into the printer syringe. Rheological studies demonstrated that the gels had a rapid and reversible modulus response to shear stress. Thus, these materials were suitable as inks for direct-write 3D printing, as they were easily extruded during printing and maintained sufficient mechanical integrity which was necessary to support the next printed layer. Printed structures of high aspect ratio pillars and stacked layers were successfully demonstrated. These types of 3D hydrogel structures may ultimately have an impact in the biomedical field for applications such as tissue engineering.
A matter of presentation: The manner in which polyvalent ligands are presented to a cell—homogeneously or in spatially defined groupings on a nanoparticle surface—may play an important role in ...cellular uptake. This aspect is investigated for the first time using a linear dendritic polymer construct to pattern the surfaces of nanoparticles with variable‐sized ligand clusters in different spatial arrangements.
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