Design of Long Circulating Nontoxic Dendritic Polymers for the Removal of Iron in Vivo

• Published in: ACS nano Vol. 7; no. 12; pp. 10704 - 10716
• Main Authors: Imran ul-haq, Muhammad, Hamilton, Jasmine L, Lai, Benjamin F. L, Shenoi, Rajesh A, Horte, Sonja, Constantinescu, Iren, Leitch, Heather A, Kizhakkedathu, Jayachandran N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-12-2013
• Subjects: Activation analysis; Animals; Biocompatibility; Biocompatible Materials; Cell Survival; Chelating; Chelating Agents - chemistry; Complement Activation; Deferoxamine - chemistry; Disease Models, Animal; Drug Design; Erythrocytes - metabolism; Female; Ferritins - chemistry; Glycerol - chemistry; Hemolysis; Human Umbilical Vein Endothelial Cells; Humans; In vivo testing; Iron; Iron - isolation & purification; Iron Overload - prevention & control; Mice; Mice, Inbred BALB C; Nanomedicine; Nanostructure; Nanotechnology; Organs; Partial Thromboplastin Time; Patients; Polymers - chemistry; Prothrombin Time; Scaffolds; Thrombelastography; Tissue Distribution; blood circulation; iron chelation; iron overload; desferoxamine (DFO); hyperbranched polyglycerol (HPG); blood compatibility
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn4035074

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 (t 1/2) in mice is defined by the structural features of the scaffold. There was a 484 fold increase in t 1/2 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.