ABSTRACT
Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.
Subject(s)
Ammonia/chemistry , Drug Carriers/chemistry , Hepatic Encephalopathy/drug therapy , Inactivation, Metabolic/genetics , Ammonia/metabolism , Butadienes/chemistry , Butadienes/pharmacology , Drug Carriers/pharmacology , Fluorescein-5-isothiocyanate/chemistry , Hemiterpenes/chemistry , Hemiterpenes/pharmacology , Hepatic Encephalopathy/etiology , Hepatic Encephalopathy/metabolism , Humans , Hydrogen-Ion Concentration , Liver Diseases/complications , Liver Diseases/drug therapy , Liver Diseases/metabolism , Methacrylates/chemistry , Particle Size , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology , Polymerization , Polymers/chemistry , Polymers/pharmacology , Proton-Motive Force/drug effects , Urea Cycle Disorders, Inborn/complications , Urea Cycle Disorders, Inborn/drug therapy , Urea Cycle Disorders, Inborn/metabolism , Water/metabolismABSTRACT
A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of sufficient size generally provide for potent anti-Mtb activity of these dihydropyridomycins (minimum inhibitory concentration (MIC) values around 2.5 µM), with several analogs thus approaching the activity of natural pyridomycin. Surprisingly, some of these compounds, in contrast to pyridomycin, are insensitive to overexpression of InhA in Mycobacterium tuberculosis (Mtb). This indicates that their anti-Mtb activity does not critically depend on the inhibition of InhA and that their overall mode of action may differ from that of the original natural product lead.
