title: Design of long circulating nontoxic dendritic polymers for the removal of iron in vivo.
abstract: Patients requiring chronic red blood cell (RBC) transfusions for inherited or acquired anemias are at risk of developing transfusional iron overload, which may impact negatively on organ function and survival. Current iron chelators are suboptimal due to the inconvenient mode of administration and/or side effects. Herein, we report a strategy to engineer low molecular weight iron chelators with long circulation lifetime for the removal of excess iron in vivo using a multifunctional dendritic nanopolymer scaffold. Desferoxamine (DFO) was conjugated to hyperbranched polyglycerol (HPG) and the plasma half-life (t1/2) in mice is defined by the structural features of the scaffold. There was a 484 fold increase in t1/2 between the DFO (5 min) versus the HPG-DFO (44 h). In an iron overloaded mouse model, efficient iron excretion by HPG-DFO in the urine and feces was demonstrated (p = 0.0002 and 0.003, respectively) as was a reduction in liver, heart, kidney, and pancreas iron content, and plasma ferritin level (p = 0.003, 0.001, 0.001, 0.001, and 0.003, respectively) compared to DFO. Conjugates showed no apparent toxicity in several analyses including body weight, serum lactate dehydrogenase level, necropsy analysis, and by histopathological examination of organs. These findings were supported by in vitro biocompatibility analyses, including blood coagulation, platelet activation, complement activation, red blood cell aggregation, hemolysis, and cell viability. This nanopolymer-based chelating system would potentially benefit patients suffering from transfusional iron overload.
authors.affiliation: Centre for Blood Research, Department of Pathology and Laboratory Medicine, and ‡Department of Chemistry, University of British Columbia , Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran ul-haq
authors.forename: Jasmine L
authors.initials: JL
authors.lastname: Hamilton
authors.forename: Benjamin F L
authors.initials: BF
authors.lastname: Lai
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Shenoi
authors.forename: Sonja
authors.initials: S
authors.lastname: Horte
authors.forename: Iren
authors.initials: I
authors.lastname: Constantinescu
authors.forename: Heather A
authors.initials: HA
authors.lastname: Leitch
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D002470:Cell Survival; D002614:Chelating Agents / Q000737:chemistry*; D003167:Complement Activation; D003676:Deferoxamine / Q000737:chemistry; D004195:Disease Models, Animal; D015195:Drug Design; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005293:Ferritins / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D006461:Hemolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007501:Iron / Q000302:isolation & purification*; D019190:Iron Overload / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine; D036103:Nanotechnology; D010314:Partial Thromboplastin Time; D011108:Polymers / Q000737:chemistry*; D011517:Prothrombin Time; D013916:Thrombelastography; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D002614:Chelating Agents; D011108:Polymers; C043941:polyglycerol; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine; D005990:Glycerol