Rational design of composition and activity correlations for pH-responsive and glutathione-reactive polymer therapeutics.
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-responsive, membrane-destabilizing polymers present a new approach to shuttling therapeutic molecules past the endosomal membrane and into the cytoplasm of targeted cells. This report describes the use of a functionalized monomer, pyridyl disulfide acrylate (PDSA), to develop pH-responsive, membrane-destabilizing, and glutathione-reactive polymers by copolymerization with several pH-responsive and hydrophobic monomers. The activity of the carriers is described as a function of (a) increasing the length of the hydrophobic alkyl group substituted onto the pH-responsive monomer and (b) the incorporation of 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 cell (RBC) hemolysis assay. Hemolysis results show that the increase in the hydrophobic character of the polymer backbone results in a shift in the pH sensitivities 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 enhancing the cytoplasmic delivery of macromolecular therapeutic.
University of Washington, Department of Bioengineering, Box: 352255, Seattle, WA 98195-2255, USA.
Mohamed E H
ME
El-Sayed
Allan S
AS
Hoffman
Patrick S
PS
Stayton
D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D004220:Disulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology
C493634:5-pyridyl-4,5-dithiapentyl acrylate; D000179:Acrylates; D004220:Disulfides; D011108:Polymers; D005978:Glutathione