Nanogel-DFO conjugates as a model to investigate pharmacokinetics, biodistribution, and iron chelation in vivo

Abstract

Deferoxamine (DFO) to treat iron overload (IO) has been limited by toxicity issues and short circulation times and it would be desirable to prolong circulation to improve non-transferrin bound iron (NTBI) chelation. In addition, DFO is currently unable to efficiently target the large pool of iron in the liver and spleen. Nanogel-Deferoxamine conjugates (NG-DFO) can prove useful as a model to investigate the pharmacokinetic (PK) properties and biodistribution (BD) behavior of iron-chelating macromolecules and their overall effect on serum ferritin levels. NG-DFO reduced the cytotoxicity of DFO and significantly reduced cellular ferritin levels in IO macrophages in vitro. PK/BD studies in normal rats revealed that NG-DFO displayed prolonged circulation and preferential accumulation into the liver and spleen. IO mice treated with NG1-DFO presented significantly lower levels of serum ferritin compared to DFO. Total renal and fecal elimination data point to the need to balance prolonged circulation with controlled degradation to accelerate clearance of iron-chelating macromolecules.

Highly chelating stellate mesoporous silica nanoparticles for specific iron removal from biological media

“…66 %. These results are higher to those of other studies conducted with DFoB grafted onto other materials such as nanogel-DFoB, which allow a capture efficiency of 50 % in vivo with ferritine (i.e., universal intracellular protein that ensures iron storage) as a source of iron 54 . An other comparison can be done with mesoporous silica type MCM-41 functionalized with DFoB that allows a capture efficiency of ca.…”

Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine

“…A promising way to increase the plasma half‐life of DFO is covalently conjugating DFO to biocompatible polymers using its terminal amino group which does not contribute to iron chelation (Figure 1A). 7 There has been extensive research in this field for iron overload diseases, 19‐21 in which polymeric DFO successfully increased the plasma half‐life of DFO and resulted in enhancing the therapeutic effect. For iron chelation cancer therapy, due to prolonged blood retention, polymeric DFO has been expected to passively target tumors through an enhanced permeability and retention (EPR) effect 7 .…”

ROS-triggered degradable iron-chelating nanogels: Safely improving iron elimination in vivo

“…3A). We have previously confirmed that nanogel-DFO macromolecules can significantly extend the circulation time of DFO,[29] therefore the decrease in serum ferritin levels may be a result of the prolonged circulation of rNG-DFO compared to free DFO. The urine and feces for the different treatment groups were collected using metabolic cages throughout the duration of the study and the total iron content present was measured by standard atomic absorption spectroscopy (AAS) to compare the iron exclusion levels for each treatment group.…”

“…We have previously demonstrated that nanogels are capable of significantly extending DFO circulation. [29] To prepare these new degradable nanogels, an activated ester–amine crosslinking methodology previously reported by Thayumanavan’s group was utilized to generate ROS-responsive nanogels [30] that were then post-functionalized with DFO. Of particular significance is that the ROS-reponsive degradation mechanism of these nanogels results from the incorporation of modified thioketal crosslinkers which have previously been shown to rapidly cleave into ketones and organic thiols (or disulfides) in the presence of ROS.…”