Functionalized dendrimers as endotoxin sponges

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 5; pp. 1295 - 1298
• Main Authors: Cromer, Jens R., Wood, Stewart J., Miller, Kelly A., Nguyen, Thuan, David, Sunil A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2005; Elsevier
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cell Line; Dendrimers; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxin; Endotoxins - antagonists & inhibitors; Endotoxins - chemistry; Endotoxins - pharmacology; Lipopolysaccharide; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - chemistry; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Mice; Molecular Structure; Nitric Oxide - biosynthesis; Pharmacology. Drug treatments; Polyamines - chemical synthesis; Polyamines - chemistry; Polyamines - pharmacology; Sepsis; Sepsis - chemically induced; Sepsis - drug therapy; Sepsis - prevention & control; Structure-Activity Relationship; Surface Properties; Lipopolysaccharide; Sepsis; Dendrimers; Endotoxin; Oxidative stress; Rodentia; In vitro; Biological activity; Amidoamine polymer; Infection; Toxin; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Complexing agent; Animal; Subcutaneous administration; Inhibition; Endotoxemia; Dendritic structure; Gram negative bacteria
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.01.026

PAMAM dendrimers with surface groups modified with hydrophobic groups sequester bacterial lipopolysaccharides. Lipopolysaccharides (LPS), otherwise termed ‘endotoxins’, are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of ‘Septic Shock’, a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. Polyamidoamine dendrimers, with the surface amines substoichiometrically derivatized with alkyl groups bind LPS with high affinity, neutralize LPS-induced inflammatory responses in vitro, and afford protection in a murine model of endotoxic shock. Dendrimers represent a new class of potentially useful compounds for the therapy of Gram-negative sepsis.