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Central nervous system (CNS) injuries persist for years, and currently there are no therapeutics that can address the complex injury cascade that develops over this time-scale. 17β-estradiol (E2) has broad tropism within the CNS, targeting and inducing beneficial phenotypic changes in myriad cells following injury. To address the unmet need for vastly prolonged E2 release, we report first-generation poly(pro-E2) biomaterial scaffolds that release E2 at nanomolar concentrations over the course of 1–10 years via slow hydrolysis in vitro. As a result of their finely tuned properties, these scaffolds demonstrate the ability to promote and guide neurite extension ex vivo and protect neurons from oxidative stress in vitro. The design and testing of these materials reported herein demonstrate the first step towards next-generation implantable biomaterials with prolonged release and excellent regenerative potential.

 

The purpose of this Viewpoint is to discuss the molecular design principles that guide development of synthetic antimicrobial polymers, especially those intended to mimic the structure of host defense peptides (HDPs). In particular, we focus on the principle of “amphiphilic balance” as it relates to some recently developed polyphosphoniums with somewhat atypical structure. We find that the fundamental concept of amphiphilic balance is still applicable to these new polymers, but that the method to achieve such balance is somewhat unique. We then briefly outline the future challenges and opportunities in this field.

 

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. 

Cationic and amphiphilic polymers are known to exert broad-spectrum antibacterial activity by a putative mechanism of membrane disruption. Typically, nonspecific binding to hydrophobic components of the complex biological milieu, such as globular proteins, is considered a deterrent to the successful application of such polymers. To evaluate the extent to which serum deactivates antibacterial polymethacrylates, we compared their minimum inhibitory concentrations in the presence and absence of fetal bovine serum. Surprisingly, we discovered that the addition of fetal bovine serum (FBS) to the assay media in fact enhances the antimicrobial activity of polymers against Gram-positive bacteria S. aureus, whereas the opposite is the case for Gram-negative E. coli. Here, we present these unexpected trends and develop a hypothesis to potentially explain this unusual phenomenon. 

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. 

ABSTRACT We synthesized precision oligomers of thiophene with cationic and hydrophobic side chains to mimic the charge, hydrophobicity, and molecular size of antibacterial host defense peptides (HDPs). In this study, the source of cationic charge was a guanidinium salt moiety intended to reflect the structure of arginine-rich HDPs. Due to the pi-conjugated oligo(thiophene) backbone structure, these compounds absorb visible light in aqueous solution and react with dissolved oxygen to produce highly biocidal reactive oxygen species (ROS). Thus, the compounds exert bactericidal activity in the dark with dramatically enhanced potency upon visible light illumination. We find that guanylation of primary amine groups enhanced the activity of the oligomers in the dark but also mitigated their light-induced activity enhancement. In addition, we also quantified their toxicity to mammalian cell membranes using a hemolysis assay with red blood cells, in the light and dark conditions. 

We utilized a templated ring-opening metathesis (TROM) strategy to synthesize a series of precision macrocyclic olefins, each containing two, three or four repeating units of a cyclooctene with pendant carboxylic acid side chains. The structures were confirmed by a combination of NMR spectroscopy, MALDI, and MALDI ms/ms fragmentation studies. In accordance with previous work, we found that cyclooctene monomers covalently tethered to precision oligo(thiophene)s yield exclusively macrocyclic products when subjected to the Grubbs 3 rd generation catalyst in highly dilute solution (10 −4 M in DCM, 0 °C). Upon hydrolytic liberation of the daughter oligo(olefin) product, further derivatization with cationic groups confers antibacterial and hemolytic activities. We compare the biological activity of these precision macrocycles to that of a polydisperse sample prepared by direct ROM in the absence of a template. Surprisingly, the relatively ill-defined, disperse mixture of oligomeric species exerted biological activity comparable to that of the precision oligomeric macrocycles, suggesting a remarkable degree of tolerance for heterogeneity. These findings provide nuance to the structure–activity relationships understood thus far for AMPs and their mimics, especially in the context of relatively underexplored macrocyclic compounds.