Abstract
Deferoxamine (DFO) is a widely used drug for the treatment of iron-overload-related diseases in the clinic. However, its inherent shortcomings, such as a short plasma half-life and cytotoxicity, need to be addressed to widen its clinical utility. In this study, PEGylated DFO was first synthesized, and its chemical structure was characterized, and then in vitro and in vivo studies were performed. The metabolism assay showed that the stability of the PEGylated DFO was significantly improved, with a half-life 20 times greater than DFO. Furthermore, the PEGylated DFO exhibited significantly lower cytotoxicity compared with DFO. Additionally, the hemocompatibility assay showed that the PEGylated DFO had no significant effect on the coagulation system, red blood cells, complement, and platelets. In vivo studies indicated that PEGylated DFO was capable of reducing the iron accumulation, degeneration of neurons, and promotion of functional recovery. Taken together, PEGylated DFO improved stability, cytotoxicity, and iron-overload in an experimental stroke model in rats, making it a promising therapy for treating iron-overload conditions in the clinic.
Highlights
Iron-overload is a serious problem that commonly presents in the clinic and is associated with many diseases such as hereditary hemochromatosis, thalassemia, Alzheimer’s disease, Parkinson’s disease, and stroke
Both products exhibited similar spectra: the broadband around 3,450 cm−1 was assigned to the N-H and O-H stretching vibrations; the band at 3,300 cm−1 was attributed to the N-H stretching vibrations, and the band at 2,880 cm−1 was assigned to the symmetric stretching vibrations of the CH2; the band at 1,650 and 1,550 cm−1 were assigned to amide I and II, respectively; the band at 1,460 cm−1 was attributed to the bending vibration of the CH2, and the band at 1,100 cm−1 was assigned to stretching vibrations of the C-O-C
Our results showed that there was no significant difference between each index in the PEGylated DFO group and that in the saline group, which indicated that PEGylated DFO had no significant effect on the coagulation system
Summary
Iron-overload is a serious problem that commonly presents in the clinic and is associated with many diseases such as hereditary hemochromatosis, thalassemia, Alzheimer’s disease, Parkinson’s disease, and stroke. This is because mammals, such as humans, cannot secrete excess iron in a controlled manner (Camaschella et al, 2020). To treat these conditions, iron chelation therapy has long been the gold standard for treatment, and one of the commonly used drugs is deferoxamine (DFO) (Holden and Nair, 2019). DFO toxicity is dose- and time-dependent, and results in complications such as cardiomyopathy, growth retardation, and endocrine dysfunction (Porter, 1997; Baath et al, 2008; Tian et al, 2016a; Guo S. et al, 2018)
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