Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers.
A class of high molecular weight iron chelators has been prepared by covalently attaching deferoxamine (DFO), by its amino group, to a variety of biocompatible polymers such as dextran and hydroxyethyl-starch. The iron-binding properties of DFO are virtually unchanged after the attachment procedure, but the toxicity and circulatory half-life are profoundly altered. Competitive iron-binding experiments indicate that the conjugates retain a high affinity for ferric iron. In addition, the derivatives inhibit iron-driven lipid peroxidation as effectively as the parent drug. However, the LD50 in mice (based on DFO equivalents) is approximately 4000 mg/kg for dextran-DFO as compared to 250 mg/kg for free DFO. Consistent with the greatly decreased LD50, intravenous administration of the conjugates in dogs at a dose of 100 mg/kg (body weight) does not cause the severe hypotension associated with intravenous administration of DFO. The plasma half-lives of these adducts are increased greater than 10-fold for dextran-DFO and hydroxyethyl-starch-DFO compared to the free drug. Finally, and most importantly, the conjugates are effective in mediating in vivo iron mobilization and excretion. Because recent evidence implicates iron as an important component of tissue injury in many disease states, these high molecular weight iron chelators may have potential for improved therapy, allowing higher sustained plasma concentrations of the active drug.
Hallaway
P E
PE
Biomedical Frontiers, Inc., Minneapolis, MN 55414.
Eaton
J W
JW
Panter
S S
SS
Hedlund
B E
BE
D000818:Animals; D001672:Biocompatible Materials; D001794:Blood Pressure / Q000187:drug effects; D003676:Deferoxamine / Q000032:analysis / Q000138:chemical synthesis / Q000633:toxicity*; D003911:Dextrans / Q000138:chemical synthesis / Q000633:toxicity*; D004285:Dogs; D006895:Hydroxyethyl Starch Derivatives / Q000138:chemical synthesis / Q000633:toxicity*; D007501:Iron; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000633:toxicity*; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D013213:Starch / Q000031:analogs & derivatives*
D001672:Biocompatible Materials; D003911:Dextrans; D006895:Hydroxyethyl Starch Derivatives; D007502:Iron Chelating Agents; C062212:dextran-deferoxamine; C062213:hydroxyethylstarch-deferoxamine; D013213:Starch; D007501:Iron; D003676:Deferoxamine