TY - JOUR
T1 - Renal clearable nanochelators for iron overload therapy
AU - Kang, Homan
AU - Han, Murui
AU - Xue, Jie
AU - Baek, Yoonji
AU - Chang, Ju Oae
AU - Hu, Shuang
AU - Nam, Ha Young
AU - Jo, Min Joo
AU - El Fakhri, Georges
AU - Hutchens, Michael P.
AU - Choi, Hak Soo
AU - Kim, Jonghan
N1 - Funding Information:
We thank Ronald Blackman and John Randle for helpful discussions and Ivey Choi for manuscript editing. This study was supported by the U.S. NIH/NHLBI #U54-HL119145 (Boston Biomedical Innovation Center) and #R01-HL143020, NIH/NIBIB #R01-EB022230, American Heart Association #17GRNT33460134, the Creative Materials Discovery Program through the National Research Foundation of Korea (2019M3D1A1078938), and the Joint Research Project for Outstanding Research Institutions funded by the Gimhae Industry Promotion and Biomedical Foundation. Work by M.P.H. was supported with resources and the use of facilities at the Portland VA Medical Center. The contents do not represent the views of the U.S. National Institutes of Health, Department of Veterans Affairs or the U.S. Government.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.
AB - Iron chelators have been widely used to remove excess toxic iron from patients with secondary iron overload. However, small molecule-based iron chelators can cause adverse side effects such as infection, gastrointestinal bleeding, kidney failure, and liver fibrosis. Here we report renal clearable nanochelators for iron overload disorders. First, after a singledose intravenous injection, the nanochelator shows favorable pharmacokinetic properties, such as kidney-specific biodistribution and rapid renal excretion (>80% injected dose in 4 h), compared to native deferoxamine (DFO). Second, subcutaneous (SC) administration of nanochelators improves pharmacodynamics, as evidenced by a 7-fold increase in efficiency of urinary iron excretion compared to intravenous injection. Third, daily SC injections of the nanochelator for 5 days to iron overload mice and rats decrease iron levels in serum and liver. Furthermore, the nanochelator significantly reduces kidney damage caused by iron overload without demonstrating DFO’s own nephrotoxicity. This renal clearable nanochelator provides enhanced efficacy and safety.
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U2 - 10.1038/s41467-019-13143-z
DO - 10.1038/s41467-019-13143-z
M3 - Article
C2 - 31723130
AN - SCOPUS:85074958112
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5134
ER -