Magnetic nanoparticles for theragnostics

Abstract

Engineered magnetic nanoparticles (MNPs) represent a cutting-edge tool in medicine because they can be simultaneously functionalized and guided by a magnetic field. Use of MNPs has advanced magnetic resonance imaging (MRI), guided drug and gene delivery, magnetic hyperthermia cancer therapy, tissue engineering, cell tracking and bioseparation. Integrative therapeutic and diagnostic (i.e., theragnostic) applications have emerged with MNP use, such as MRI-guided cell replacement therapy or MRI-based imaging of cancer-specific gene delivery. However, mounting evidence suggests that certain properties of nanoparticles (e.g., enhanced reactive area, ability to cross cell and tissue barriers, resistance to biodegradation) amplify their cytotoxic potential relative to molecular or bulk counterparts. Oxidative stress, a 3-tier paradigm of nanotoxicity, manifests in activation of reactive oxygen species (ROS) (tier I), followed by a proinflammatory response (tier II) and DNA damage leading to cellular apoptosis and mutagenesis (tier III). Invivo administered MNPs are quickly challenged by macrophages of the reticuloendothelial system (RES), resulting in not only neutralization of potential MNP toxicity but also reduced circulation time necessary for MNP efficacy. We discuss the role of MNP size, composition and surface chemistry in their intracellular uptake, biodistribution, macrophage recognition and cytotoxicity, and review current studies on MNP toxicity, caveats of nanotoxicity assessments and engineering strategies to optimize MNPs for biomedical use.

Figure 1. Examples of MNPs of different size, composition and surface chemistry

Transmission electron microscopy (TEM) of A, maghemite (Fe₂O₃) nanoparticles coated with anionic DMSA forming ~ 8-nm-thick round-shaped AMNPs. B, magnetite (Fe₃O₄) of ~8-nm-think core coated with ~2-nm-thick gold (Au), forming core-shell nanoparticles. C, magnification x 50 of B. (D). Silica coated Fe₃O₄ nanoparticles of ~ 100 nm, synthesized by sol gel method.

Figure 2. Anionic DMSA-coated MNPs promote macrophage infiltration in nerve

Plastic-embedded transverse rat sciatic nerve sections after intrafascicular injection of DMSA-coated MNPs (B) or DMSA (A). Stained with Methylene blue Azure II. A. Uniform axonal morphology typical of uninjured nerve and no evidence of infiltrating immune cells is seen after DMSA (control coating) injection. B. Increased incidence of infiltrating macrophages (yellow arrows), particularly in the perivascular spaces, is noted after DMSA-coated MNP injection. Note pixilated MNPs phagocytosed within macrophages and axonal myelin splitting (red asterisks) at the interface with MNP-filled macrophages. Objective magnification x 100 (scale bar = 25 μm). Legend: a, myelinated axon; v, vessel; red asterisks, myelin splitting; yellow arrow, infiltrating macrophages.

Figure 3. A proposed mechanism of MNP-induced macrophage recruitment into neuronal tissues

(1) Exposure to cytotoxic MNPs stimulated the formation of ROS in resident cells. (2) ROS promotes expression and release of proinflammatory cytokines, such as TNF-α. Through its two receptors (TNFR), TNF-α activates p38 and ERK mitogen-activated protein kinases pathways to (3) induce the expression of matrix metalloproteinases (MMPs) in its inactive, pro-MMP form. In addition, (4) ROS can directly promote MMP activation from pro-form. MMPs are the only enzymes in the body capable of degrading blood-brain and blood-nerve barriers (BBB/BNB), which (5) promotes infiltration of circulating macrophages (mΦ) into neuronal tissues. MNP size and surface chemistry determines the mechanisms and the target cells of MNP internalization, as well as extent of neurotoxicity of MNPs.