Biodistribution and toxicity of epitope‐functionalized dextran iron oxide nanoparticles in a pregnant murine model

Abstract

In pursuit of a preventive therapeutic for maternal autoantibody‐related (MAR) autism, we assessed the toxicity, biodistribution, and clearance of a MAR specific peptide‐functionalized dextran iron oxide nanoparticle system in pregnant murine dams. We previously synthesized ~15 nm citrate‐coated dextran iron oxide nanoparticles (DIONPs), surface‐modified with polyethylene glycol and MAR peptides to produce systems for nanoparticle‐based autoantibody reception and entrapments (SNAREs). First, we investigated their immunogenicity and MAR lactate dehydrogenase B antibody uptake in murine serum in vitro. To assess biodistribution and toxicity, as well as systemic effects, we performed in vivo clinical and post mortem pathological evaluations. We observed minimal production of inflammatory cytokines—interleukin 10 (IL‐10) and IL‐12 following in vitro exposure of macrophages to SNAREs. We established the maximum tolerated dose of SNAREs to be 150 mg/kg at which deposition of iron was evident in the liver and lungs by histology and magnetic resonance imaging but no concurrent evidence of liver toxicity or lung infarction was detected. Further, SNAREs exhibited slower clearance from the maternal blood in pregnant dams compared to DIONPs based on serum total iron concentration. These findings demonstrated that the SNAREs have a prolonged presence in the blood and are safe for use in pregnant mice as evidenced by no associated organ damage, failure, inflammation, and fetal mortality. Determination of the MTD dose sets the basis for future studies investigating the efficacy of our nanoparticle formulation in a MAR autism mouse model.

Proteomics unite traditional toxicological assessment methods to evaluate the toxicity of iron oxide nanoparticles

“…Toxicokinetic analysis showed that IONPs exhibited an appropriate elimination rate and a favorable dose-response relationship in the blood after intravenous administration. The tissue distribution results indicated that IONPs were delivered to a range of organ systems after entering the systemic circulation, in accordance with the results from numerous studies (Yu et al, 2018;Gaharwar et al, 2019;Bolandparvaz et al, 2020). In the present study, the highest IONPs deposition in the spleen and liver indicated that these two organs played the most important role in IONPs elimination from the systemic circulation.…”

In Vitro and In Vivo Biological Assays of Dextran Coated Iron Oxide Aqueous Magnetic Fluids

“…In addition, aspects related to the biodistribution of iron oxide nanoparticles coated with different materials have been studied recently [ 34 , 35 , 36 , 37 , 38 , 39 ]. In their study regarding the “Genotoxicity and biocompatibility of superparamagnetic iron oxide nanoparticles: influence of surface modification on biodistribution, retention, DNA damage and oxidative stress”, Gosh et al [ 34 ] reported the use of poly (lactic-co-glycolic acid) together with either didodeclydimethyl-ammonium-bromide or α-tocopheryl-polyethleneglycol-succinate in order to reduce the cytogenotoxicity and the generation of reactive oxygen species of iron oxide nanoparticles.…”

The Intrinsic Biological Identities of Iron Oxide Nanoparticles and Their Coatings: Unexplored Territory for Combinatorial Therapies

“…These complex interactions between the biological milieu and the nanoparticle depend on multiple factors such as synthetic identity, the biological microenvironment, and the interaction time with the organism. The possibility of functionalizing IONPs with biomolecules such as peptides [ 14 , 15 ], ligands [ 16 ], antibodies [ 17 , 18 ], aptamers [ 19 , 20 ], or RNAs [ 21 ] further enables IONPs to interact with a specific cell type or tissue; for instance, antibody-functionalized IONPs can specifically target antigen-expressing tumor cells, which allows local application of an alternative magnetic field for the induction of magnetic hyperthermia [ 22 ]. Understanding these interactions and how they influence the intended application of the synthesized nanoparticle is critical, as such knowledge not only allows for more rational nanomaterial design but could also enable these previously undiscovered characteristics to be harnessed for combinatorial therapies.…”