A new pH-responsive and glutathione-reactive, endosomal membrane-disruptive polymeric carrier for intracellular delivery of biomolecular drugs.
In this study, we have designed, synthesized and characterized a novel pH-responsive polymeric carrier for the enhanced cytoplasmic delivery of enzyme susceptible drugs, such as antisense oligonucleotides, proteins and peptides. A novel functionalized monomer, pyridyl disulfide acrylate, was synthesized and incorporated into an amphiphilic copolymer consisting of methacrylic acid and butyl acrylate, which resulted in a glutathione- and pH-sensitive, membrane-disruptive terpolymer with functional groups, that allow thiol-containing molecules to be readily conjugated. Conjugation and/or ionic complexation with oligopeptides or antisense oligonucleotides were performed and characterized. Hemolytic activity at low pHs remained high even after the conjugation/complexation with oligopeptides and asODNs. This polymer showed no toxicity, as determined with mouse 3T3 fibroblasts and human THP-1 macrophage-like cells. Uptake of the radiolabeled polymer and enhanced cytoplasmic delivery of FITC-ODN was also studied in THP-1 macrophage-like cells.
Bulmus
Volga
V
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
Woodward
Monica
M
Lin
Lianne
L
Murthy
Niren
N
Stayton
Patrick
P
Hoffman
Allan
A
D016475:3T3 Cells; D000179:Acrylates / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D002250:Carbon Radioisotopes; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000009:adverse effects / Q000138:chemical synthesis; D004337:Drug Carriers / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D011992:Endosomes / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008689:Methacrylates / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011108:Polymers / Q000009:adverse effects* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics
C493634:5-pyridyl-4,5-dithiapentyl acrylate; D000179:Acrylates; D002250:Carbon Radioisotopes; D004220:Disulfides; D004337:Drug Carriers; D008689:Methacrylates; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D010455:Peptides; D011108:Polymers; D013438:Sulfhydryl Compounds; C032490:n-butyl acrylate; D005978:Glutathione; D016650:Fluorescein-5-isothiocyanate