title: Bioinspired pH-responsive polymers for the intracellular delivery of biomolecular drugs.
abstract: The biotechnology and pharmaceutical industries have developed a wide variety of potential therapeutics based on the molecules of biology: DNA, RNA, and proteins. While these therapeutics have tremendous potential, effectively formulating and delivering them have also been a widely recognized challenge. A variety of viruses and toxins have evolved multi-functional biomolecules to solve this problem by directing cellular uptake and enhancing biomolecular transport to the cytoplasm from the low pH endosomal compartment. In the study reported here, we have designed and synthesized bio-inspired, pH-responsive polymeric carriers, which we call "encrypted polymers", that mimic the multi-functional design of biology. These encrypted polymers target and direct cellular uptake, as well as enhance cytosolic delivery by disrupting endosomal membranes in a pH-dependent fashion. We show that the encrypted polymeric carriers significantly enhance the delivery of oligonucleotides and peptides to the cytoplasm of cultured macrophages, demonstrating the potential of this approach for delivery of biotherapeutics and vaccines.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle 98195, USA.
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: Jean
authors.initials: J
authors.lastname: Campbell
authors.forename: Nelson
authors.initials: N
authors.lastname: Fausto
authors.forename: Allan S
authors.initials: AS
authors.lastname: Hoffman
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
mesh_terms: D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013343:Styrenes / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D007202:Indicators and Reagents; D009841:Oligonucleotides; D010455:Peptides; D011108:Polymers; D013343:Styrenes; D011092:Polyethylene Glycols; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II