Enzymatically Biodegradable Polyrotaxane-Deferoxamine Conjugates for Iron Chelation.
Chelation therapy is frequently used to help reduce excess iron in the body, but current chelators such as deferoxamine (DFO) are plagued by short blood circulation times, which necessitates infusions and can cause undesirable toxic side effects in patients. To address these issues, polyrotaxanes (PR) were synthesized by threading α-cyclodextrin (α-CD) onto poly(ethylene glycol) bis(amine) (PEG-BA, MW 3400 g/mol) capped with enzymatically cleavable bulky Z-L phenylalanine (Z-L Phe) moieties. The resulting PR was conjugated to DFO and hydroxypropylated to generate the final polyrotaxane-DFO (hPR-DFO). The iron chelating capability of hPR-DFO was verified by UV-vis absorption spectroscopy and the ability of materials to degrade into smaller CD-conjugated DFO fragments (hCD-DFO) in the presence of the protease was confirmed via gel permeation chromatography. In vitro studies in iron-overloaded macrophages reveal that hPR-DFO can significantly reduce the cytotoxicity of the drug while maintaining its chelation efficacy, and that it is more rapidly endocytosed and trafficked to lysosomes of iron-overloaded cells in comparison to non-iron-overloaded macrophages. In vivo studies indicate that iron-overloaded mice treated with hPR-DFO displayed lower serum ferritin levels (a measure of iron burden in the body) and could eliminate excess iron by both the renal and fecal routes. Moreover, there was no gross evidence of acute toxicological damage to the liver or spleen.
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia , Athens, Georgia 30602-2352, United States.
Zhi
Z
Liu
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison , Madison, Wisconsin 53705-2222, United States.
Tien-Min
TM
Lin
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia , Athens, Georgia 30602-2352, United States.|Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison , Madison, Wisconsin 53705-2222, United States.
Max
M
Purro
Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia , Athens, Georgia 30602-2352, United States.
May P
MP
Xiong
D000818:Animals; D015913:Chelation Therapy; D003676:Deferoxamine / Q000737:chemistry*; D007501:Iron; D007502:Iron Chelating Agents; D019190:Iron Overload; D051379:Mice; D043862:Rotaxanes / Q000737:chemistry*
D007502:Iron Chelating Agents; D043862:Rotaxanes; D007501:Iron; D003676:Deferoxamine
biodegradable; chelation therapy; deferoxamine; iron overload; polyrotaxane