Magnetic nanoparticles for theragnostics☆
Introduction
Nanotechnology is at the leading edge of the rapidly developing new therapeutic and diagnostic concepts in all areas of medicine [1]. Magnetic nanoparticles (MNPs) are a class of nanoparticles (i.e., engineered particulate materials of < 100 nm) that can be manipulated under the influence of an external magnetic field. MNPs are commonly composed of magnetic elements, such as iron, nickel, cobalt and their oxides.
The unique ability of MNPs to be guided by an external magnetic field has been utilized for magnetic resonance imaging (MRI), targeted drug and gene delivery, tissue engineering, cell tracking and bioseparation [2], [3], [4], [5]. When further “functionalized” with drugs and bioactive agents, such as peptides and nucleic acids, MNPs form distinct particulate systems that penetrate cell and tissue barriers and offer organ-specific therapeutic and diagnostic modalities [4]. The ability of MNPs to be functionalized and concurrently respond to a magnetic field has made them a useful tool for theragnostics — the fusion of therapeutic and diagnostic technologies that targets to individualize medicine [6]. Through multilayered functionalization, MNPs can simultaneously act as diagnostic molecular imaging agents [7], [8] and drug carriers. MNP-based MRI imaging has been already combined with cell replacement therapy [9], organ-specific gene delivery [10], intra-operative tumor removal surgery [11], [12] and other applications discussed below. However, the resulting variety of MNP composition, shape, size, surface chemistry and state of dispersion each may influence their biodistribution and toxic potential [3].
The increased toxic potential of nano-sized materials relative to their bulk and molecular counterparts is owed to their largely enhanced reactive surface area, ability to cross cell and tissue barriers, and resistance to biodegradation [13]. Activation of oxidative stress and inflammatory signaling leading to apoptosis and genotoxicity are the key paradigm(s) of nanotoxicity [14], [15], [16], [17], [18]. In an in vivo setting, macrophages of the defense reticuloendothelial system (RES) quickly challenge and internalize MNPs, neutralizing their cytotoxic potential [5]. But in order to promote their circulation time, engineering strategies to modify MNP surface chemistry are used to allow for evasion of macrophages [5]. Therefore, an integrative approach to advancing MNP designs and understanding their interface with specific organ systems, with regards to their application and safety, are imperative to advancing nanomedicine [14], [16], [17], [18].
Several recent reviews have discussed engineering designs, physiochemical characteristics [19], [20] and biomedical applications of MNP [3], [4], [5]. Here, we will review current studies of MNP toxicity and issues relevant to the development of the discipline of magnetic nanotoxicology.
Section snippets
Formulations of MNPs for biomedical applications
Iron oxide MNPs, such as magnetite Fe3O4 or its oxidized and more stable form of maghemite γ-Fe2O3, are superior to other metal oxide nanoparticles for their biocompatibility and stability and are, by far, the most commonly employed MNPs for biomedical applications [2], [3], [4], [21], [22]. Thus, we here refer to iron oxide MNPs as “MNPs”, unless otherwise specified. Typically, magnetic nanoparticles are synthesized and dispersed into homogenous suspensions, called ferrofluids, composed of a
Surface chemistry and biocompatibility
Without a coating, MNPs have hydrophobic surfaces with large surface area to volume ratios and a propensity to agglomerate [19]. A proper surface coating allows iron oxide MNPs to be dispersed into homogenous ferrofluids and improve MNP stability. Several groups of coating materials are used to modify MNP surface chemistry:
- a.
organic polymers, such as dextran, chitosan, polyethylene glycol, polysorbate, polyaniline
- b.
organic surfactants, such as sodium oleate and dodecylamine
- c.
inorganic metals, such as
MNPs for theragnostic platforms
Theragnostics (the fusion of therapeutic and diagnostic approaches) aims to personalize and advance medicine [6]. MNPs represent a particularly appropriate tool based on their ability to be simultaneously functionalized and guided by an external magnetic field. Novel designs have focused on sophisticated multilayering of MNPs with the goal to develop controlled nanodelivery systems. Already, functionalized MNPs have been used in combination theragnostic approaches for gene delivery with
MNP metabolism
Typically, upon their intracellular internalization via endocytosis, MNPs are clustered within lysosomes where, presumably, they are degraded into iron ions by an array of hydrolyzing enzymes at low pH according to endogenous iron metabolism pathways [3]. MNP size, charge, surface chemistry and route of delivery each influence their circulation time and biodistribution patterns in the body [5]. Large (> 200 nm) particles are usually sequestered by the spleen via mechanical filtration followed by
Conclusions
Potential benefits of nanotechnology in medicine are inimitable owing to refined, highly targeted, blood–brain barrier-crossing drug delivery and imaging platforms, unique transfection, labeling, bioseparation, as well as analytical and tissue engineering approaches. The versatility of superparamagnetic iron oxide MNPs is owed to their capability to respond to an external magnetic field and be functionalized with bioactive agents at the same time and/or differentially. Challenges to the rapidly
Glossary
- AMNP
- Anionic (DMSA-coated) MNP
- Au–MNP
- Gold-coated MNP
- BBB
- Blood–brain barrier
- BNB
- Blood–nerve barrier
- BrdU
- 5-bromo-2-deoxyuridine
- CNS
- Central nervous system
- DMSA
- Dimercaptosuccinic acid
- HO-1
- Heme-oxygenase 1
- i.v.
- Intravenous injection
- MMP
- Matrix metalloproteinase
- MNP
- Magnetic nanoparticles
- NP
- Nanoparticle
- OS
- Oxidative stress
- RES
- Reticuloendothelial system
- ROS
- Reactive oxygen species
- SQUID
- Superconducting quantum interference device
- TEM
- Transmission electron microscopy
- TNF-α
- Tumor necrosis factor alpha
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Identifying and Assessing Biomaterial Nanotoxicity in Translational Research for Preclinical Drug Development”.