Acrylic copolymers with appropriate compositions of counits having cationic charge with 2-carbon and 6-carbon spacer arms can show superior antibacterial activities with concomitant very low hemolytic effect. These amphiphilic copolymers represent one of the most promising synthetic polymer antibacterial systems reported.
Amphiphilic acrylic copolymers with
hexamethyleneamine and poly(ethylene glycol) side chains can show
>100-fold selectivity toward Escherichia coli over
red blood cells. Homopolymer with cationic pendant amine groups is
highly hemolytic and antibacterial. Incorporation of approximately
33 mol % of poly(ethylene glycol) methyl ether methacrylate (PEGMA)
led to 1300 times reduction in hemolytic activity, while maintaining
high levels of antibacterial activity. The hemolytic activity of these
PEGylated copolymers depends on the overall content and spatial distribution
of the PEGMA units. Higher activity against Escherichia coli than Staphylococcus aureus was observed for this
polymer system, likely due to hydrogen bonding ability of the PEG
side chains with polysaccharide cell wall of the bacteria. Field emission
scanning electron microscopy analysis confirmed the bacterial membrane
rupture activity exerted by these copolymers, whereas time-kill studies
revealed significantly different bactericidal kinetics toward the
Gram-negative Escherichia coli and the Gram-positive Staphylococcus aureus.
The effects of variation in the topographical position of the cationic center and hydrophobic segments on the antibacterial and hemolytic activities of polyacrylates.
Synthetic amphiphilic polymers have been established as potentially efficient agents to combat widespread deadly infections involving antibiotic resistant superbugs. Incorporation of poly(ethylene glycol) (PEG) side chains into amphiphilic copolymers can reduce their hemolytic activity while maintaining high antibacterial activity. Our study found that the incorporation of PEG has substantially different effects on the hemolytic and antibacterial activities of copolymers depending on structural variations in the positions of cationic centers relative to hydrophobic groups. The PEG side chains dramatically reduced the hemolytic activities in copolymers with hydrophobic hexyl and cationic groups on the same repeating unit. However, in case of terpolymers with cationic and lipophilic groups placed on separate repeating units, the presence of PEG has significantly lower effect on hemolytic activities of these copolymers. PEGylated terpolymers displayed substantially lower activity against Staphylococcus aureus (S. aureus) than Escherichia coli (E. coli) suggesting the deterring effect of S. aureus’ peptidoglycan cell wall against the penetration of PEGylated polymers. Time-kill studies confirmed the bactericidal activity of these copolymers and a 5 log reduction in E. coli colony forming units was observed within 2 h of polymer treatment.
In
pharmaceutical oral drug delivery development, about 90% of
drugs in the pipeline have poor aqueous solubility leading to severe
challenges with oral bioavailability and translation to effective
and safe drug products. Amorphous solid dispersions (ASDs) have been
utilized to enhance the oral bioavailability of poorly soluble active
pharmaceutical ingredients (APIs). However, a limited selection of
regulatory-approved polymer excipients exists for the development
and further understanding of tailor-made ASDs. Thus, a significant
need exists to better understand how polymers can be designed to interact
with specific API moieties. Here, we demonstrate how an automated
combinatorial library approach can be applied to the synthesis and
screening of polymer excipients for the model drug probucol. We synthesized
a library of 25 random heteropolymers containing one hydrophilic monomer
(2-hydroxypropyl acrylate (HPA)) and four hydrophobic monomers at
varied incorporation. The performance of ASDs made by a rapid film
casting method was evaluated by dissolution using ultra-performance
liquid chromatography (UPLC) sampling at various time points. This
combinatorial library and rapid screening strategy enabled us to identify
a relationship between polymer hydrophobicity, monomer hydrophobic
side group geometry, and API dissolution performance. Remarkably,
the most effective synthesized polymers displayed slower drug release
kinetics compared to industry standard polymer excipients, showing
the ability to modulate the drug release profile. Future coupling
of high throughput polymer synthesis, high throughput screening (HTS),
and quantitative modeling would enable specification of designer polymer
excipients for specific API functionalities.
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