Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Nicole I. Hunter
Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Chemistry, Duke University, Durham, NC 27710, USA
Rachel E. Rempel
Department of Surgery, Duke University, Durham, NC 27710, USA
Haixiang Yu
Department of Surgery, Duke University, Durham, NC 27710, USA
Diane M. Spencer
Department of Medicine and Immunology, Division of Rheumatology, Duke University Medical Center, Durham, NC 27710, USA
Cynthia Z. Sullenger
Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Biology, Duke University, Durham, NC 27710, USA
William S. Greene
Collegiate School, New York, NY 10069, USA
Anastasia K. Varanko
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA
Seyed A. Eghtesadi
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA
Ashutosh Chilkoti
Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA
David S. Pisetsky
Department of Medicine and Immunology, Division of Rheumatology, Duke University Medical Center, Durham, NC 27710, USA; Medical Research Service, Veterans Administration Medical Center, Durham, NC 27705, USA
Jeffrey I. Everitt
Department of Pathology, Duke University, Durham, NC 27710, USA
Bruce A. Sullenger
Department of Surgery, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA; Corresponding author
Summary: Nucleic acid-binding polymers can have anti-inflammatory properties and beneficial effects in animal models of infection, trauma, cancer, and autoimmunity. PAMAM G3, a polyamidoamine dendrimer, is fully cationic bearing 32 protonable surface amines. However, while PAMAM G3 treatment leads to improved outcomes for mice infected with influenza, at risk of cancer metastasis, or genetically prone to lupus, its administration can lead to serosal inflammation and elevation of biomarkers of liver and kidney damage. Variants with reduced density of cationic charge through the interspersal of hydroxyl groups were evaluated as potentially better-tolerated alternatives. Notably, the variant PAMAM G3 50:50, similar in size as PAMAM G3 but with half the charge, was not toxic in cell culture, less associated with weight loss or serosal inflammation after parenteral administration, and remained effective in reducing glomerulonephritis in lupus-prone mice. Identification of such modified scavengers should facilitate their development as safe and effective anti-inflammatory agents.
