title: Rational design of composition and activity correlations for pH-sensitive and glutathione-reactive polymer therapeutics.
abstract: Limited cytoplasmic delivery of enzyme-susceptible drugs remains a significant challenge facing the development of protein and nucleic acid therapies that act in intracellular compartments. "Smart" pH-sensitive, membrane-destabilizing polymers present an attractive approach to shuttle therapeutic molecules past the endosomal membrane and into the cytoplasm of targeted cells. This report describes the use of a new functionalized monomer, pyridyl disulfide acrylate (PDSA), to develop pH-sensitive, membrane-destabilizing, and glutathione-reactive polymers by copolymerization with several pH-sensitive and hydrophobic monomers. The activity of the carriers is described as a function of (a) the influence of increasing the length of the hydrophobic alkyl group substituted onto the pH-sensitive monomer and (b) of the effect of incorporating a hydrophobic monomer such as butyl acrylate (BA) on the pH sensitivity and membrane-destabilizing activity of new polymer compositions. The membrane-destabilizing activity of different polymer compositions was evaluated as a function of pH and polymer concentration using the red blood cells (RBC) hemolysis assay. Hemolysis results show that the increase in the hydrophobic character of polymer backbone results in a shift in the pH sensitivity profile and an increase in the membrane-destabilizing activity. Results show that the observed hemolytic activities and pH sensitivity profiles could be designed across a range that matches the properties needed for drug carriers to enhance the cytoplasmic delivery of therapeutic cargos.
authors.affiliation: University of Washington, Department of Bioengineering, Box: 352255, AERL 338, Seattle, WA 98195-2255, USA.
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: El-Sayed
authors.forename: Allan S
authors.initials: AS
authors.lastname: Hoffman
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D004220:Disulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008970:Molecular Weight; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C493634:5-pyridyl-4,5-dithiapentyl acrylate; D000179:Acrylates; D004220:Disulfides; D011108:Polymers; D005978:Glutathione