ferrihydrite and Neoplasms

Magnetosomes are magnetite nanoparticles biosynthesized by magnetotactic bacteria. Given their potential clinical applications for the diagnosis and treatment of cancer, it is essential to understand what becomes of them once they are within the body. With this aim, here we have followed the intracellular long-term fate of magnetosomes in two cell types: cancer cells (A549 cell line), because they are the actual target for the therapeutic activity of the magnetosomes, and macrophages (RAW 264.7 cell line), because of their role at capturing foreign agents. It is shown that cells dispose of magnetosomes using three mechanisms: splitting them into daughter cells, excreting them to the surrounding environment, and degrading them yielding less or non-magnetic iron products. A deeper insight into the degradation mechanisms by means of time-resolved X-ray absorption near-edge structure (XANES) spectroscopy has allowed us to follow the intracellular biotransformation of magnetosomes by identifying and quantifying the iron species occurring during the process. In both cell types there is a first oxidation of magnetite to maghemite and then, earlier in macrophages than in cancer cells, ferrihydrite starts to appear. Given that ferrihydrite is the iron mineral phase stored in the cores of ferritin proteins, this suggests that cells use the iron released from the degradation of magnetosomes to load ferritin. Comparison of both cellular types evidences that macrophages are more efficient at disposing of magnetosomes than cancer cells, attributed to their role in degrading external debris and in iron homeostasis.

Topics: Ferritins; Iron; Macrophages; Magnetosomes; Neoplasms

The rapid elimination of systemically administered drug nanocarriers by the mononuclear phagocyte system (MPS) compromises nanomedicine delivery efficacy. To mitigate this problem, an approach to block the MPS has been introduced and implemented by intravenous pre-administering blocker nanoparticles. The required large doses of blocker nanoparticles appeared to burden the MPS, raising toxicity concerns. To alleviate the toxicity issues in MPS blockade, we propose an intrinsically biocompatible blocker, ferrihydrite - a metabolite ubiquitous in a biological organism. Ferrihydrite particles were synthesized to mimic endogenous ferritin-bound iron. Ferrihydrite surface coating with carboxymethyl-dextran was found to improve MPS blockade dramatically with a 9-fold prolongation of magnetic nanoparticle circulation in the bloodstream and a 24-fold increase in the tumor targeted delivery. The administration of high doses of ferrihydrite caused low toxicity with a rapid recovery of toxicological parameters after 3 days. We believe that ferrihydrite particles coated with carboxymethyl-dextran represent superior blocking biomaterial with enviable biocompatibility.

Topics: Dextrans; Ferric Compounds; Humans; Macrophages; Nanoparticles; Neoplasms

We designed and synthesized a modified ferritin as a tumor-environment-responsive nanocarrier. We found that this nanocarrier could evolve its surface properties upon sensing a tumor-associated protease, matrix metalloproteinase-2 (MMP-2), which initiated agglomeration, resulting in the enhancement of T(2) relaxivity for magnetic resonance imaging (MRI). The designed ferritin contained a triad of modifiers composed of (i) a "sensing" segment (substrate peptide of MMP-2), (ii) "hydrophobic" segments and (iii) a "hydrophilic" segment of polyethylene glycol (PEG). The hydrophilic segment ensured the particles' monodispersibility in aqueous conditions. In the presence of MMP-2 activity, the "sensing" segment was cleaved by the enzyme and its submerged "hydrophobic" segments were exposed on the surface, resulting in the initiation of aggregation. Because ferritin contains ferrihydrite in its inner space, this multimerization resulted in the enhancement of T(2) relaxivity, suggesting that this nanocarrier may be useful as a contrast agent in MRI.

Topics: Amino Acid Sequence; Animals; Contrast Media; Ferric Compounds; Ferritins; Humans; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Imaging; Matrix Metalloproteinase 2; Microscopy, Electron, Transmission; Nanoparticles; Neoplasm Proteins; Neoplasms; Oligopeptides; Peptide Fragments; Polyethylene Glycols; Substrate Specificity; Surface Properties