Hydroxamic acid-containing hydrogels for nonabsorbed iron chelation therapy: synthesis, characterization, and biological evaluation.
Iron overload is a severe clinical condition and can be largely prevented by the use of iron-specific chelating agents. A successful iron chelator needs to be orally active, nontoxic, and selective. In this study, hydrogels containing pendant hydroxamic acid groups have been synthesized as potential nonabsorbed chelators for iron in the gastrointestinal tract. The synthetic method employed to introduce hydroxamic acid groups to polymer chains involved reaction of polymer gels based on N-acryloxysuccinimide, acryloyl chloride, and (2-hydroxyethyl)acrylate monomers with hydroxylamine. These hydroxamic acid-functionalized polymer gels swell favorably in water and effectively sequester iron. In vitro iron-binding properties of these hydrogels were evaluated from their binding isotherms by use of iron(II) alone and in the presence of other competing metal ions. These polymers bind iron over a broad pH range. The iron-binding properties of the polymers were found to depend on the concentration of hydroxamate groups on polymer chains. The in vivo iron-binding efficacy of the polymers was evaluated in rat as the animal model. The polymers prevented an increase in serum hemoglobin and hematocrit levels in the animals, thus suggesting the prevention of systemic absorption of dietary iron from the gastrointestinal tract. The animals also maintained normal body weight during the treatment period, indicating the absence of any apparent toxicity associated with these polymers.
Polomoscanik
Steven C
SC
Drug Discovery and Development, Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451, USA.
Cannon
C Pat
CP
Neenan
Thomas X
TX
Holmes-Farley
S Randall
SR
Mandeville
W Harry
WH
Dhal
Pradeep K
PK
D000178:Acrylamides / Q000737:chemistry; D000179:Acrylates / Q000737:chemistry; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D015913:Chelation Therapy / Q000379:methods; D004952:Esters; D041981:Gastrointestinal Tract / Q000378:metabolism; D006400:Hematocrit; D006454:Hemoglobins / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000737:chemistry*; D019811:Hydroxylamine / Q000737:chemistry; D007477:Ions; D007501:Iron / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry*; D019266:Iron, Dietary / Q000378:metabolism; D008024:Ligands; D008297:Male; D008670:Metals; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D020058:Styrene / Q000737:chemistry; D013388:Succinimides / Q000737:chemistry; D013997:Time Factors
D000178:Acrylamides; D000179:Acrylates; D002614:Chelating Agents; D004952:Esters; D006454:Hemoglobins; D020100:Hydrogels; D006877:Hydroxamic Acids; D007477:Ions; D007502:Iron Chelating Agents; D019266:Iron, Dietary; D008024:Ligands; D008670:Metals; D011108:Polymers; D013388:Succinimides; C035957:2-hydroxyethyl acrylate; D019811:Hydroxylamine; D020058:Styrene; C026200:acryloyl chloride; D007501:Iron