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Renally‐Clearable Polymeric Nanochelator for Iron Overload Therapy
Author(s) -
Han Murui,
Kang Homan,
Xue Jie,
Choi Hak Soo,
Kim Jonghan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.571.7
Subject(s) - deferoxamine , chelation therapy , chemistry , chelation , in vivo , pharmacology , dextran , conjugated system , nuclear chemistry , biochemistry , medicine , inorganic chemistry , microbiology and biotechnology , organic chemistry , biology , polymer
Iron (Fe) is an essential metal, but high Fe stores are toxic and cause heart and liver failures, arthritis, and diabetes. Since there is no recognized active pathway for Fe excretion, disposing extra Fe from the body is the primary therapeutic goal of treating patients with iron overload (IO). While the chelation therapy has been widely used to alleviate IO, Fe chelators have serious adverse effects, such as hypotension, gastrointestinal bleeding, kidney failure and liver fibrosis, likely due to non‐specific distribution in off‐target tissues. Consequently, there is an unmet need for a new therapeutic strategy for IO. Here we developed an ultrasmall nanoparticle (NP) that covalently binds to an FDA‐approved Fe chelator deferoxamine (DFO), which limits the distribution into off‐target tissues, while efficiently capturing excess Fe. We first generated renally‐clearable ɛ‐poly‐L‐lysine (EPL) conjugated with zwitterionic near‐infrared fluorophore ZW800. We then produced DFO‐coated NP by conjugating four DFO molecules on the surface of each EPL with balanced charges (DFO4‐NP). The ferrozine competition assay demonstrated that the association constant of DFO4‐NP to Fe was greater by a 3.5‐fold (p<0.001) compared to native DFO, indicating improved Fe binding affinity after conjugation. Next, in vivo chelation efficacy of DFO4‐NP (2 μmol as NP/kg) was determined in IO mice induced by intraperitoneal injection of Fe dextran (100 mg/kg). Urinary Fe content collected over 4 h post‐dose was increased by a 2.5‐fold (p<0.001) and by an 8.6‐fold (p<0.001) after intravenous (i.v.) and subcutaneous (s.c.) injection of DFO4‐NP, respectively, compared to blank NP. Similarly, renal clearance of Fe was increased by a 2.8‐fold (p<0.001) and a 9.5‐fold (p<0.001) after i.v. and s.c. of DFO4‐NP, respectively, compared to NP alone. Moreover, when compared to equimolar dose of native DFO, DFO4‐NP showed increased urinary recovery and renal clearance of Fe by a 2.8‐fold (p=0.003) and by a 2.5‐fold (p=0.003), respectively. These suggest the greater chelation efficiency and urinary excretion of Fe by s.c. DFO‐NP administration than by native DFO or blank NP. We further evaluated the efficacy of DFO4‐NP after s.c. doses daily for 5 d in dietary IO mice. DFO4‐NP decreased non‐heme Fe content in serum (22%, p=0.010), liver (26%, p=0.011) and spleen (26%, p=0.011) compared to blank NP. Consistently, DFO4‐NP decreased the status of an Fe‐storage protein ferritin (Ftn), a reliable marker of body Fe stores, in both liver (28%, p=0.041) and spleen (35%, p=0.024), compared to blank NP. These results indicate that DFO‐NPs efficiently remove excess Fe stores from plasma and tissues after repeated administrations. Moreover, H&E staining showed a decreased density of tubular cells in the kidney after native DFO treatment, while no kidney damage was observed in mice treated with NP alone or DFO4‐NP. Taken together, the renally‐clearable DFO‐NPs provide improved therapeutic efficacy against physiological complications resulting from IO disorders, while minimizing the inherent toxicity of small molecule chelators. Support or Funding Information NIH U54 HL119145, American Heart Association17GRNT33460134 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .