Abstract
Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells.
Highlights
Interactions between β -cyclodextrin (β -CD) and ferrocene (Fc) (Figs S1, S2 and S3) are introduced into the nanogel polymerization cocktail in the form of “host-guest crosslinkers (CL)”[23] and polymerized in the presence of acrylamide (AAm) and DFO monomers (DFOm) (Fig. S4) by a free radical initiator in reverse emulsion reaction chambers (Fig. 1)
This is due to oxidation of the hydrophobic Fc guest to the more hydrophilic Ferrocenium cation (Fc+) which significantly reduces its interaction with the β -CD hydrophobic host cavity[24]
By keeping the ratio of CL to AAm to initiator fixed at 1:75:0.3 and varying only the DFOm molar ratio from 5–0.5, DFO density within the final resulting nanogels could be controlled
Summary
Interactions between β -cyclodextrin (β -CD) and ferrocene (Fc) (Figs S1, S2 and S3) are introduced into the nanogel polymerization cocktail in the form of “host-guest crosslinkers (CL)”[23] and polymerized in the presence of acrylamide (AAm) and DFO monomers (DFOm) (Fig. S4) by a free radical initiator in reverse emulsion reaction chambers (Fig. 1). The resulting nanomaterial is characterized by DFO moieties for binding to iron and crosslinked by host-guest interactions between β -CD and Fc. In the presence of oxidizing agents such as hydrogen peroxide (H2O2), the CL holding the nanogel scaffold together begins to degrade at an oxidative stress-dependent rate. In the presence of oxidizing agents such as hydrogen peroxide (H2O2), the CL holding the nanogel scaffold together begins to degrade at an oxidative stress-dependent rate This is due to oxidation of the hydrophobic Fc guest to the more hydrophilic Ferrocenium cation (Fc+) which significantly reduces its interaction with the β -CD hydrophobic host cavity[24]. The overall synthetic methodology can generate macromolecules in the size range appropriate for drug delivery applications
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