- Award ID(s):
- 1653418
- NSF-PAR ID:
- 10077535
- Date Published:
- Journal Name:
- Journal of Materials Chemistry B
- ISSN:
- 2050-750X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Melissa Grunlan (Ed.)The performance of antimicrobial polymers depends sensitively on the type of cationic species, charge density, and spatial arrangement of cations. Here we report antimicrobial polymers bearing unusually bulky tetraaminophosphonium groups as the source of highly delocalized cationic charge. The bulky cations drastically enhanced the biocidal activity of amphiphilic polymers, leading to remarkably potent activity in the submicromolar range. The cationic polynorbornenes with pendent tetraaminophosphonium groups killed over 98% E. coli at a concentration of 0.1 μg/mL and caused a 4-log reduction of E. coli within 2 h at a concentration of 2 μg/mL, showing very rapid and potent bactericidal activity. The polymers are also highly hemolytic at similar concentrations, indicating a biocidal activity profile. Polymers of a similar chemical structure but with more flexible backbones were made to examine the effects of the flexibility of polymer chains on their activity, which turned out to be marginal. We also explore variants with different spacer arm groups separating the cations from the backbone main chain. The antibacterial activity was comparably potent in all cases, but the polymers with shorter spacer arm groups showed more rapid bactericidal kinetics. Interestingly, pronounced counterion effects were observed. Tightly bound PF6– counteranions showed poor activity at high concentrations due to gross aggregate formation and precipitation from the assay media, whereas loosely bound Cl– counterions resulted in very potent activity that monotonically increased with increasing concentration. In this paper, we reveal that bulky phosphonium cations are associated with markedly enhanced biocidal activity, which provides an innovative strategy to develop more effective self-disinfecting materials.more » « less
-
Herein we report the synthesis of ternary statistical methacrylate copolymers comprising cationic ammonium (amino-ethyl methacrylate: AEMA), carboxylic acid (propanoic acid methacrylate: PAMA) and hydrophobic (ethyl methacrylate: EMA) side chain monomers, to study the functional role of anionic groups on their antimicrobial and hemolytic activities as well as the conformation of polymer chains. The hydrophobic monomer EMA was maintained at 40 mol% in all the polymers, with different percentages of cationic ammonium (AEMA) and anionic carboxylate (PAMA) side chains, resulting in different total net charge for the polymers. The antimicrobial and hemolytic activities of the copolymer were determined by the net charge of +3 or larger, suggesting that there was no distinct effect of the anionic carboxylate groups on the antimicrobial and hemolytic activities of the copolymers. However, the pH titration and atomic molecular dynamics simulations suggest that anionic groups may play a strong role in controlling the polymer conformation. This was achieved via formation of salt bridges between cationic and anionic groups, transiently crosslinking the polymer chain allowing dynamic switching between compact and extended conformations. These results suggest that inclusion of functional groups in general, other than the canonical hydrophobic and cationic groups in antimicrobial agents, may have broader implications in acquiring functional structures required for adequate antimicrobial activity. In order to explain the implications, we propose a molecular model in which formation of intra-chain, transient salt bridges, due to the presence of both anionic and cationic groups along the polymer, may function as “adhesives” which facilitate compact packing of the polymer chain to enable functional group interaction but without rigidly locking down the overall polymer structure, which may adversely affect their functional roles.more » « less
-
Abstract The present study expands the versatility of cationic poly(2‐oxazoline) (POx) copolymers as a polyethylene glycol (PEG)‐free platform for gene delivery to immune cells, such as monocytes and macrophages. Several block copolymers are developed by varying nonionic hydrophilic blocks (poly(2‐methyl‐2‐oxazoline) (pMeOx) or poly(2‐ethyl‐2‐oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2‐isopropyl‐2‐oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2‐methoxy‐carboxyethyl‐2‐oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2‐aminoethyl)amine (TREN). For the attachment of a targeting ligand, mannose, azide‐alkyne cycloaddition click chemistry methods are employed. Of the two cationic side chains, polyplexes made with DET‐containing copolymers transfect macrophages significantly better than those made with TREN‐based copolymer. Likewise, nontargeted pEtOx‐based diblock copolymer is more active in cell transfection than pMeOx‐based copolymer. The triblock copolymer with hydrophobic block iPrOx performs poorly compared to the diblock copolymer which lacks this additional block. Surprisingly, attachment of a mannose ligand to either copolymer is inhibitory for transfection. Despite similarities in size and design, mannosylated polyplexes result in lower cell internalization compared to nonmannosylated polyplexes. Thus, PEG‐free, nontargeted DET‐, and pEtOx‐based diblock copolymer outperforms other studied structures in the transfection of macrophages and displays transfection levels comparable to GeneJuice, a commercial nonlipid transfection reagent.
-
Fundamental synthetic methodology was advanced to allow for the preparation of a reactive glucose-based block copolycarbonate, which was conveniently transformed into a series of amphiphilic block copolymers that underwent aqueous assembly into functional nanoparticle morphologies having practical utility in biomedical and other applications. Two degradable d -glucose carbonate monomers, with one carrying alkyne functionality, were designed and synthesized to access well-defined block polycarbonates ( Đ < 1.1) via sequential organocatalytic ring opening polymerizations (ROPs). Kinetic studies of the organocatalyzed sequential ROPs showed a linear relationship between the monomer conversion and the polymer molecular weight, which indicated the controlled fashion during each polymerization. The pendant alkyne groups underwent two classic click reactions, copper-catalyzed azide–alkyne dipolar cycloaddition (CuAAC) and thiol–yne addition reactions, which were employed to render hydrophilicity for the alkyne-containing block and to provide a variety of amphiphilic diblock poly( d -glucose carbonate)s (PGCs). The resulting amphiphilic PGCs were further assembled into a family of nanostructures with different sizes, morphologies, surface charges and functionalities. These non-ionic and anionic nanoparticles showed low cytotoxicity in RAW 264.7 mouse macrophage cells and MC3T3 healthy mouse osteoblast precursor cells, while the cationic nanoparticles exhibited significantly higher IC 50 (162 μg mL −1 in RAW 264.7; 199 μg mL −1 in MC3T3) compared to the commercially available cationic lipid-based formulation, Lipofectamine (IC 50 = 31 μg mL −1 ), making these nanomaterials of interest for biomedical applications.more » « less
-
We report the synthesis of cationic dendrons (1 st and 2 nd generations) with pendant alkyl chains of varying lengths (C 8 , C 12 , C 14 ), which are classified as cationic molecular umbrellas. In each case, the dendron surface moieties were functionalized with guanidine groups, which are fully protonated in aqueous media of pH 7.4, lending cationic character to the solute. We found that these compounds are potent membrane-disrupting antibacterial agents with dose-dependent hemolytic activities. Confocal microscopy confirmed the permeabilization of E. coli and S. aureus cell membranes. A pyrene emission assay confirms that the dendrons are unimolecularly solvated at the concentrations relevant to their antibacterial activity, although they do aggregate at higher concentrations in aqueous buffer. Most importantly, when we compare the activity of these guanidinium-functionalized umbrellas to our previously published data on ammonium-functionalized analogues, we found no significant benefits to guanidinium relative to the ammoniums. The antibacterial activities are similar in all cases tested, and the highest selectivity index was found in the ammonium series, which stands in contrast to many other classes of antibacterial agents for which guanidinylation is typically associated with enhanced activity and selectivity.more » « less