Body iron homeostasis can only be regulated through balance of dietary iron, chelating it to proteins, or by storing it in RES organs (bone marrow, spleen, and liver). For this reason, chelators (whether i.v. or oral) must rely on renal clearance and fecal elimination to remove excess iron from the body. The significance of this proposal could be wide-ranging for a variety of diseases that relies on chelation therapy to alleviate symptoms of metal overload, since small molecule metal chelators have traditionally suffered from a short residence time in the body and unspecific organ targeting. In this proposal, we will specifically investigate nanoparticles for chelation of transfusional iron overload. Surprisingly, there are only three FDA-approved small molecule chelators available for treating iron overload and there is a need for new and improved technology. In order to achieve a sufficient window of therapy, a balance between renal clearance and pharmacokinetics should be achieved, which current small molecule chelators currently lack. Nanotechnology has already dramatically demonstrated that it can be used to improve the pharmacokinetics of small molecule drugs, with enhanced efficacy and specificity of therapies through the use of targeting ligands. We are the first lab, to the best of our knowledge, to investigate novel designs of nanoparticles we call "lipoGels" for chelation of iron. LipoGels can pick up both forms of iron, Fe2+ and Fe3+, which is critical for iron chelation therapy. Another unique aspect of our innovative technology is that lipoGels can be consistently fabricated and tailored to desired in vivo behavior. Advantages include prolonged circulation, lower doses, and targeting via ligands to organs as desired, while attempting to balance renal and fecal elimination of iron-bound degradation products. We believe that this is an exciting project with potential to push the field of chelation therapy forward.
The aims i n this proposal are to 1) systematically prepare and characterize lipoGels for in vivo chelation of iron, 2) investigate the mechanism of iron chelation in vitro, and maximum tolerated dose, pharmacokinetics, and biocompatibility/safety of lipoGels in vivo, and 3) test the iron chelation efficacy of optimized lipoGels in rat models of iron overload.

Public Health Relevance

In this proposal, we will investigate nanoparticles for chelation of transfusional iron overload. LipoGels can pick up both forms of iron, Fe2+ and Fe3+, which is critical for iron chelation therapy. Nanoparticles can be consistently fabricated and tailored t desired in vivo behavior. Advantages include prolonged circulation, lower doses, and targeting via ligands to organs as desired, while attempting to balance renal and fecal elimination of iron-bound degradation products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099596-02
Application #
8680233
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Bishop, Terry Rogers
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$291,019
Indirect Cost
$95,269
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715