Influence of magnetic nanoparticle biotransformation on contrasting efficiency and iron metabolism.

Magnetic nanoparticles are widely used in biomedicine for MRI imaging and anemia treatment. The aging of these nanomaterials in vivo may lead to gradual diminishing of their contrast properties and inducing toxicity. Here, we describe observation of the full lifecycle of 40-nm magnetic particles from their injection to the complete degradation in vivo and associated impact on the organism. We found that in 2 h the nanoparticles were eliminated from the bloodstream, but their initial biodistribution changed over time. In 1 week, a major part of the nanoparticles was transferred to the liver and spleen, where they degraded with a half-life of 21 days. MRI and a magnetic spectral approach revealed preservation of contrast in these organs for more than 1 month. The particle degradation led to the increased number of red blood cells and blood hemoglobin level due to released iron without causing any toxicity in tissues. We also observed an increase in gene expression level of Fe-associated proteins such as transferrin, DMT1, and ferroportin in the liver in response to the iron particle degradation. A deeper understanding of the organism response to the particle degradation can bring new directions to the field of MRI contrast agent design.

Macrophage blockade using nature-inspired ferrihydrite for enhanced nanoparticle delivery to tumor.

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.

Long-Term Fate of Magnetic Particles in Mice: A Comprehensive Study.

Safe application of nanoparticles in medicine requires full understanding of their pharmacokinetics including catabolism in the organism. However, information about nanoparticle degradation is still scanty due to difficulty of long-term measurements by invasive techniques. Here, we describe a magnetic spectral approach for in vivo monitoring of magnetic particle (MP) degradation. The method noninvasiveness has allowed performing of a broad comprehensive study of the 1-year fate of 17 types of iron oxide particles. We show a long-lasting influence of five parameters on the MP degradation half-life: dose, hydrodynamic size, ζ-potential, surface coating, and internal architecture. We observed a slowdown in MP biotransformation with an increase of the injected dose and faster degradation of the particles of a small hydrodynamic size. A comparison of six types of 100 nm particles coated by different hydrophilic polymer shells has shown that the slowest (t1/2 = 38 ± 6 days) and the fastest (t1/2 = 15 ± 4 days) degradations were achieved with a polyethylene glycol and polyglucuronic acid coatings, respectively. The most significant influence on the MP degradation was due to the internal architecture of the particles as the coverage of magnetic cores with a solid 39 nm polystyrene layer slowed down the half-life of the core-shell MPs from 48 days to more than 1 year. The revealed deeper insights into the particle degradation in vivo may facilitate rational design of nano- and microparticles with predictable long-term fate in vivo.