Magnetic nanoparticles in MR imaging and drug delivery☆
Introduction
Magnetic nanoparticles (MNPs) are a major class of nanoscale materials with the potential to revolutionize current clinical diagnostic and therapeutic techniques. Due to their unique physical properties and ability to function at the cellular and molecular level of biological interactions, MNPs are being actively investigated as the next generation of magnetic resonance imaging (MRI) contrast agents [1] and as carriers for targeted drug delivery [2], [3]. Although early research in the field can be dated back several decades, the recent surge of interest in nanotechnology has significantly expanded the breadth and depth of MNP research. With a wide range of applications in the detection, diagnosis, and treatment of illnesses, such as cancer [4], cardiovascular disease [5], and neurological disease [6], MNPs may soon play a significant role in meeting the healthcare needs of tomorrow.
Numerous forms of MNP with various chemical compositions have been proposed and evaluated for biomedical applications to exploit nanoscale magnetic phenomena, such as enhanced magnetic moments and superparamagnetism. Like other nanomaterial-based systems, advances in nanotechnology now allow for precise engineering of the critical features of these fine particles. Composition, size, morphology and surface chemistry can now be tailored by various processes to not only improve magnetic properties but also affect the behavior of nanoparticles in vivo [7], [8]. In its simplest form, a biomedical MNP platform is comprised of an inorganic nanoparticle core and a biocompatible surface coating that provides stabilization under physiological conditions. Additionally, the application of suitable surface chemistry allows for the integration of functional ligands [9]. This modular design enables MNPs to perform multiple functions simultaneously, such as in multimodal imaging [10], drug delivery and real-time monitoring, as well as combined therapeutic approaches.
The ability of MNPs to enhance proton relaxation of specific tissues and serve as MR imaging contrast agents is one of the most promising applications of nanomedicine. MNPs in the form of superparamagnetic iron oxides (SPIO) have been actively investigated as MR imaging contrast agents for over two decades [11]. With applications, such as bowel contrast agents (i.e., Lumiren® and Gastromark®) and liver/spleen imaging (i.e., Endorem® and Feridex IV®) [12], [13], already on the market, SPIOs have led the way for MNPs into the clinic. Several forms of ultrasmall superparamagnetic iron oxides (USPIO) have undergone clinical trials with one of the most notable being Combidex® which is in late stage clinical trials for use in the detection of lymph node metastases [14].
As therapeutic tools, MNPs have been evaluated extensively for targeted delivery of pharmaceuticals through magnetic drug targeting (MDT) [15], [16] and by active targeting through the attachment of high affinity ligands [17], [18], [19]. In the spirit of Ehrlich's “Magic Bullet” [20], MNPs have the potential to overcome limitations associated with systemic distribution of conventional chemotherapies. With the ability to utilize magnetic attraction and/or specific targeting of disease biomarkers, MNPs offer an attractive means of remotely directing therapeutic agents specifically to a disease site, while simultaneously reducing dosage and the deleterious side effects associated with non-specific uptake of cytotoxic drugs by healthy tissue. Also referred to as magnetic targeted carriers (MTC), colloidal iron oxide particles in early clinical trials have demonstrated some degree of success with the technique and shown satisfactory toleration by patients [21], [22]. Although not yet capable of reaching levels of safety and efficacy for regulatory approval, pre-clinical studies indicated that some of the shortcomings of MDT technology, such as poor penetration depth and diffusion of the released drug from the disease site, can be overcome by improvements in MTC design [23], [24]. Furthermore, the use of MNP as carriers in multifunctional nanoplatforms as a means of real-time monitoring of drug delivery is an area of intense interest [25], [26].
A significant challenge associated with the application of these MNP systems is their behavior in vivo. The efficacy of many of these systems is often compromised due to recognition and clearance by the reticuloendothelial system (RES) prior to reaching target tissue, as well as by an inability of to overcome biological barriers, such as the vascular endothelium or the blood brain barrier. The fate of these MNP upon intravenous administration is highly dependent on their size, morphology, charge, and surface chemistry. These physicochemical properties of nanoparticles directly affect their subsequent pharmacokinetics and biodistribution [27]. To increase the effectiveness of MNPs, several techniques, including reducing size and grafting non-fouling polymers, have been employed to improve their “stealthiness” and increase their blood circulation time to maximize the likelihood of reaching targeted tissues [28], [29].
Next-generation MNP-based MR imaging contrast agents and carriers for drug delivery incorporate novel nanocrystalline cores, coating materials, and functional ligands to improve the detection and specific delivery of these nanoparticles. New formulations of MNP cores, such as doped iron oxide nanocrystals, metallic/alloy nanoparticles, and nanocomposites, offer high magnetic moments increasing their signal-to-background ratios under MRI. Concurrently, the use of new surface coatings, such as stable gold or silica shell structures, allows for the application of otherwise toxic core materials, as well as more thorough coating through the formation of self-assembled monolayers (SAMS) on the nanoparticle surface. In addition, recent studies and reviews indicate an increasing role of cellular mechanics in diseases such as malaria [30], [31] and cancer metastasis [32], [33], [34]. As such, there is potential for next-generation platforms to incorporate surface qualities that would enable probing and/or monitoring of local physical mechanistic changes at a length scale that would greatly assist in improving disease detection, monitoring, and treatment.
Although many are still early in pre-clinical evaluation, with work still necessary to address the metabolism and potential long-term toxicity of these MNPs, efforts such as that of the National Cancer Institute (NCI) Nanotechnology Characterization Laboratory (NCL) are accelerating the evaluation of these new nanomaterials allowing for even quicker development in this already rapidly growing field. This review examines some of the recent developments in MNP technology and provides a brief background of their applications as MR imaging contrast agents and as carriers for drug delivery.
Section snippets
Magnetic properties
The penetration of magnetic fields through human tissue and the ability to remotely detect or manipulate magnetic materials have been investigated for use in medicine for centuries [35]. One of the more recent and significant applications of these properties has been in MRI as a non-invasive imaging modality capable of providing high resolution anatomical images. However, the potential of current clinical medical imaging can be greatly expanded through the use of MNPs to improve differentiation
Polymeric coatings
Surface coatings are an integral component of all MNP platforms for biomedical applications. Although not attracted magnetically, due to their superparamagnetic properties, nanoparticles still have a significant tendency to agglomerate as a result of their high surface energy. Colloidal electrostatic stabilization arising from repulsion of surface charges on the nanoparticles is typically not adequate to prevent aggregation in biological solutions due to the presence of salts or other
Blood half-life
The need to extend nanoparticles' blood circulation time to allow for their accumulation in target tissues has long been recognized as one of the primary challenges in the development of MNPs [29]. The ability to evade uptake by the RES is critical to achieving a long blood half-life. Like other colloidal carriers, the physicochemical properties of these MNP platforms, such as size, morphology, charge, and surface chemistry, dictate their fate in vivo.
The overall size of MNPs must be
Magnetic properties and MRI contrast enhancement
MR imaging is one of the most powerful non-invasive imaging modalities utilized in clinical medicine today [160], [161]. MR imaging is based on the property that hydrogen protons will align and process around an applied magnetic field, B0. Upon application of a transverse radiofrequency (rf) pulse, these protons are perturbed from B0. The subsequent process through which these protons return to their original state is referred to as the relaxation phenomenon. Two independent processes,
Magnetic drug targeting (MDT)
The primary shortcoming of most chemotherapeutic agents is their relative non-specificity and thus potential side effects to healthy tissues. To overcome this problem, MDT utilizes the attraction of MNP carriers to an external magnetic field to increase site-specific delivery of therapeutic agents [2], [3]. In general, this process involves the attachment of a cytotoxic drug to a biocompatible MNP carrier (a.k.a. magnetic targeted carrier or MTC), intravenous injection of these MTCs in the form
Conclusions
The development of MNPs has been greatly accelerated in the past decade by advances in nanotechnology, molecular cell biology, and small-animal imaging instrumentation. MNPs of various formulations have been developed to diagnose and treat diseases for which conventional therapy has shown limited efficacy. In particular, the use of MNPs as MRI contrast agents and drug carriers has drawn enormous attention, as it holds great potential of providing new opportunities for early cancer detection and
Acknowledgements
This work was supported in part by NIH/NCI Nanoplatform grant (R01CA119408), NIH/NCI grant (R01CA134213), and NIH/NIBIB grant (R01EB006043).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Inorganic Nanoparticles in Drug Delivery”.