Engineering Iron Oxide Nanoparticles for Clinical Settings

Abstract

Iron oxide nanoparticles (IONPs) occupy a privileged position among magnetic nanomaterials with potential applications in medicine and biology. They have been widely used in preclinical experiments for imaging contrast enhancement, magnetic resonance, immunoassays, cell tracking, tissue repair, magnetic hyperthermia and drug delivery. Despite these promising results, their successful translation into a clinical setting is strongly dependent upon their physicochemical properties, toxicity and functionalization possibilities. Currently, IONPs-based medical applications are limited to the use of non-functionalized IONPs smaller than 100 nm, with overall narrow particle size distribution, so that the particles have uniform physical and chemical properties. However, the main entry of IONPs into the scene of medical application will surely arise from their functionalization possibilities that will provide them with the capacity to target specific cells within the body, and hence to play a role in the development of specific therapies. In this review, we offer an overview of their basic physicochemical design parameters, giving an account of the progress made in their functionalization and current clinical applications. We place special emphasis on past and present clinical trials.

Keywords: Drug Delivery; IONP; Iron Oxide Nanoparticles; MRI; Magnetic Hyperthermia; Nanomedicine; SPION; USPION; VSPION.

Figure 1.

Membrane deformation for (a) shallow wrapping and (b) deep wrapping of a cubic-shaped nanoparticle. The network of edges and triangles describes the membrane shape and has been used for the numerical calculation of the curvature energy. [Adapted with permission from S. Dasgupta, et al., Nano Letters 14(2) (2014) 687–693. Copyright 2014 American Chemical Society]. (c) Values of diffusion length (l_diff) of nanoparticles as a function of particle size (R) at fixed values of aspect ratio (a) [Reprinted with permission from X. Li, Journal of Applied Physics, vol. 111 (2012) 024702. Copyright 2012, AIP Publishing LLC]. (d) Normalized absorption rate of cylindrical particles with different diameters and aspect ratios [Permission pending].

Figure 2.

Schematic representation of the theoretical magnetic regimes (superparamagnetic, single domain, multidomain) expected for both magnetite and maghaemite, along with some relevant applications as a function of the particle size. (*) Magnetofection is a trademark of Christian Bergemann and Dr Christian Plank. (**) Refers to uncoated, single nanoparticles. The size ranges represented are approximate and comprise the most common cases.

Figure 3.

Functionalization of IONPs Schematic representation to scale of IONPs and the structure of different molecules used for their functionalization Structures represented: IONPs doxorubicin RGD peptide (PDB ID: 3VI4) chlorotoxin (PDB ID: 1CHL) azurin p28 peptide (PDB ID: 4AZU) Nucant (N6L) [52] aptamer (PDB ID 4HQU) and antibody (PDB ID: 1IGT).

Figure 4.

A. Different internalization pathways of IONPs in mammalian cells. Possible mechanisms of uptake including macropinocytosis, caveolae- and clathrin-mediated endocytosis, phagocytosis, passive diffusion and other endocytosis pathways. After internalization, IONPs can produce cytotoxicity effects via a Fenton reaction. Hydroxyl radicals generated could damage DNA, proteins or lipids (8-OH-dG = 8 hydroxydeoxyguanosine, MDA = malondialdehyde, HNE = 4-hydroxy-2-nonenal), triggering genotoxicity. B. IONP administration in the human body, such as intrathecal, intratumoural, intravenous and intramuscular or subcutaneous methods.

Figure 5.

Organ distribution of systemically injected nanoparticles. a. Common organ distribution is shown as a function of particle size. b. Example of the ^99mTc-labeled graft copolymer used in a human patient and ⁸⁹Zr-labeled cross-linked dextran nanoparticles used in a mouse model. This figure was reproduced with permission from Nature Materials [126].