title: Thermosensitive nanoparticles with pH-triggered degradation and release of anti-inflammatory cell-penetrating peptides.
abstract: Poly(N-isopropylacrylamide-2-acrylamido-2-methyl-1-propanesulfonate) [poly(NIPAm-AMPS)] nanoparticles can be cross-linked with hydrolytically degradable N,O-dimethacryloyl hydroxylamine (DMHA) in order to yield a pH-sensitive drug delivery system that slowly erodes above pH 5.0. Varying the composition of degradable DMHA and nondegradable MBA cross-linking allows for engineered variation of particle size and degradation kinetics. Utilizing sulfated comonomer AMPS provides for increased passive loading of anti-inflammatory mitogen-activated protein kinase-activated protein kinase 2 (MK2)-inhibiting cell-penetrating peptide KAFAKLAARLYRKALARQLGVAA (KAFAK) between 24.3% and 29.2% (w/w) for nanoparticles with 5 mol % cross-linker. Nanoparticles were shown to be nontoxic in vitro and were effective at delivering a therapeutically active dose of KAFAK to THP1 human monocytes to suppress tumor necrosis factor α (TNF-α) expression during lipopolysaccharide (LPS)-induced inflammation. This thermosensitive nanoparticle system is an excellent platform for passive diffusive loading in deionized water and release in physiologically relevant ionic strength media of environmentally sensitive peptide therapeutics.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, United States.
authors.forename: Rush L
authors.initials: RL
authors.lastname: Bartlett
authors.forename: Alyssa
authors.initials: A
authors.lastname: Panitch
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D006898:Hydroxylamines / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D053769:Nanocapsules / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D010316:Particle Size; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000178:Acrylamides; D000893:Anti-Inflammatory Agents; D057846:Cell-Penetrating Peptides; D003432:Cross-Linking Reagents; D006898:Hydroxylamines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D053769:Nanocapsules; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2