The traditional iron chelator deferoxamine (DFO) has been widely used in the treatment of iron overload disease. However, DFO has congenital disadvantages, including a very short circular time and non-negligible toxicity. Herein, we designed a novel multi-arm conjugate for prolonging DFO duration in vivo and reducing cytotoxicity. The star-like 8-arm-polyethylene glycol (8-arm-PEG) was used as the macromolecular scaffold, and DFO molecules were bound to the terminals of the PEG branches via amide bonds. The conjugates displayed comparable iron binding ability to the free DFO. Furthermore, these macromolecule conjugates could significantly reduce the cytotoxicity of the free DFO, and showed satisfactory iron clearance capability in the iron overloaded macrophage RAW 246.7. The plasma half-life of the 8-arm-PEG-DFO conjugate was about 190 times than that of DFO when applied to an intravenously administered rat model. In conclusion, research indicated that these star-like PEG-based conjugates could be promising candidates as long circulating, less toxic iron chelators.Pharmaceutics 2020, 12, 329 2 of 13 pharmacokinetics (PK) of DFO was thus regarded as a promising approach to promote therapeutic efficacy and mitigate the side effects.Many attempts have been conducted by conjugating DFO to a water-soluble polymer to improve its PK properties. For example, the hyper-branched glycerol was used to form conjugates with DFO, which made it possible to chelate iron efficiently and prolong the circulation time of API in the blood [7,15,16]. Specially, the circulation half-life (t 1/2 ) of DFO was increased by up to 44 h in mice, a 484-fold increase compared to native DFO. Nevertheless, it has not yet been pursued in clinical study, probably due to the limitations of the excipients and cumbersome synthesis methods. Other DFO macromolecular conjugates, such as polyrotaxane-DFO and dextran-DFO conjugate, also showed efficacies in iron chelation and rather low cell toxicities [17,18]. However, the reported t 1/2 was prolonged to be a moderate level (~1 h). The PEG has been used in the many products since it was approved by the FDA as a pharmaceutical polymer material [19][20][21]. The PEGylation conjugates provide a solution to increase the stability of drugs and prolong their blood circulation. Tremendous efforts have been devoted to create PEG-based solutions for improving the defect of the DFO. In previous studies, the DFO was conjugated to the copolymer with the PEG side chain or the PEG based three-arm macromolecule, for designing the biocompatible, long-circulating macromolecule iron-chelator [22,23]. These polymer conjugates, however, suffered from the wide molecular range and low loading efficacy of API, making the following translations difficult. Recently, multi-armed PEGs have gained much attention in both academic and industrial fields, due to their superiority in drug-loading efficacies compared to the traditional linear PEG [24][25][26]. Herein, we successfully synthesized and designed an 8-arm-polyethylene glycol-...