Nanomedicine’s promising therapy: magnetic drug targeting

Keywords::

• drug delivery
• magnetic drug targeting
• nanomedicine
• nanoparticles
• stents

During the last decade, nanotechnology has been applied to medicine with the aim of providing improvements in diagnosis and therapy, resulting in a new discipline often referred to as nanomedicine. By conjugating drugs, imaging/contrast agents and/or cells to nano-sized devices capable of homing for targets in the body, nanomedicine has the potential to revolutionize drug delivery, medical imaging and tissue engineering. Site-directed drug targeting using nano-sized vehicles is attractive for the administration of drugs that are costly, toxic or prone to provoke side effects when given systemically. The approach provides a high local drug concentration to the diseased tissue with minimal exposure to other parts of the body. Targeting can be accomplished by conjugating ligands or antibodies, homing for biomarkers present at the target site, to the drug-loaded nanoparticles. Most research efforts to date have focused on cancer treatment [1]. An alternative targeting strategy is magnetic attraction. Although the initial attempts to manipulate devices in the body with extracorporeal magnets started in the 1950s [2–5], it is only owing to recent advancements in nanotechnology that interest in magnetic drug targeting has grown. The method involves intravascular injection of magnetic nanoparticles, transportation of the particles with the blood, and subsequent capture at the target site by the influence of a magnetic field. Unless the final target is within the vessel lumen, the particles must have the ability to penetrate the vascular wall. The challenge of magnetic drug targeting is to reach large vessels at deep locations in the body with small (nano-sized) magnetic particles. In this article, various aspects that need to be addressed during the development of magnetic drug targeting systems in order to facilitate translation into clinical practice and subsequent commercialization are highlighted.

Two key devices are required for magnetic targeting: the magnetic particles and the extracorporeal magnet source. The choice of the devices is decisive for the final outcome. The term magnetic particles is often used arbitrarily for particles that are magnetized when placed in a magnetic field. It is desirable that zero coercivity is shown – that is, no remanescent magnetization after removal of the external magnet. Such (super)paramagnetic behavior may be obtained with single-domain nanoparticles composed of ferrimagnetic or ferromagnetic materials. The magnetization depends on the magnetic susceptibility of the material and strengthens with increasing magnetic field until saturation is reached. The most commonly used materials for (bio)medical applications are two magnetic iron oxides: magnetite (Fe₃O₄) and maghemite (γ-Fe₂O₃). Magnetite has a higher magnetic saturation than maghemite and therefore is easier to attract with a magnet [6]. The saturation magnetization of iron oxide nanoparticles is often lower than that observed for the bulk material owing to various surface effects [7]. To maintain a high magnetic susceptibility, it is essential to prevent oxidation to low- or non-magnetic iron oxides. Furthermore, for medical applications the nanoparticles must be nontoxic, biocompatible and remain nonaggregated in the blood. Statistical models that relate the chemical and physical properties of the nanoparticles to their toxicity, assessed by a range of in vitro tests, may facilitate optimization and decision-making during development [8]. The stability and biocompatibility may be engineered by surface coating [9]. The surface character, as well as the size of the particles, affects the biodistribution and the clearance of the particles after their injection. Unless the final target of the nanoparticles is within the reticuloendothelial system (the lymph nodes, spleen and liver), the nanoparticles should be engineered to provide a stealth character to escape uptake by phagocytic cells. To target nanoparticles beyond the vessel lumen, cell-penetrating peptides or receptor ligands may be attached to the particle surface to facilitate cell membrane penetration and receptor-mediated endocytosis.

The method of choice for attaching drugs to nanoparticles is dependent upon the properties of the drug, target location and desired drug-release profile. The drug may be either embedded in the coating, or covalently or noncovalently associated with the particle surface. Drug action at the target location occurs either while the drug is still associated to the particle or after release. The degradation and/or excretion of nanoparticles are important aspects to consider during development to ensure safety. Physiologically based pharmacokinetic models may facilitate the process [10].

For efficient retention of particles at the target site, the attractive magnetic forces exerted on the particles must overcome the drag forces produced by the blood flow. The magnetic force on a particle of diameter d is proportional to d², while the drag force, according to Stoke’s law, is proportional to d. Based upon this principle, large particles are more easily retained with an external magnet. Furthermore, the drag force is proportional to the velocity of the blood. Many studies on magnetic targeting have consequently been carried out with relatively large (often micron-sized) particles aiming for small blood vessels. The diameter of the blood capillaries (typically 5–10 µm) limits the size of particles that can be applied without risking occlusion. For the development of safe clinical applications, nano-sized particles are more attractive.

The magnetic force exerted on a particle is proportional to both the external magnetic field and the field gradient. The magnetic field diminishes with the cube of the distance; deep locations are considerably more difficult to target than superficial ones. The majority of studies have therefore focused on superficial tissues. The strength of the magnetic field depends on the type of magnet used. The field obtained close to the surface of a strong permanent neodymium magnet is sufficient to magnetically saturate iron oxide nanoparticles. To produce more powerful magnetic fields that reach locations further from the magnet, electromagnets or even superconducting magnets may be used. However, these magnets often produce more homogeneous magnetic fields – that is, the field gradients over the target site are low. Increasing the magnetic field with a stronger magnet will not necessarily increase the magnetic force on the magnetic particles. Another aspect to consider in the choice of the magnet source is the accessibility; permanent magnets or small electromagnets are more affordable and easier to manage and position than superconducting magnets. The need for powerful magnets has already resulted in novel solutions and further improvements are to be expected [11–13].

A powerful strategy to increase the magnetic force is implanting a magnetizable object at the target site to create high local field gradients. Mathematical modeling studies have validated that the implant enhances the magnetic force on the magnetic particles up to several orders of magnitude [14–20]. In vitro studies have demonstrated that capture of magnetic particles at the surface of an implant, such as a vascular stent, placed in a magnetic field is feasible at the flow rates present in human arteries [17]. The method, referred to as implant-assisted magnetic targeting or high-field gradient magnetic targeting, relies on the concept used in high-gradient magnetic separators in the mineral processing industry [21]. Although stent implantation by percutaneous coronary intervention has revolutionized the treatment of cardiovascular disease, the procedure has given rise to several complications: restenosis due to intimal hyperplasia is predominantly observed in bare-metal stents while an increased risk of thrombosis has been found in second-generation stents – that is, the drug-eluting stents. Implant-assisted magnetic targeting was recently demonstrated in vivo for the treatment of various stent-related complications:

• • Re-endothelization of the artery wall by targeting endothelial cells loaded with magnetic nanoparticles to stented rat carotid arteries [22];

• • Antiproliferative treatment to prevent in-stent restenosis by targeting paclitaxel-loaded nanoparticles to stented rat carotid arteries [23];

• • Thrombolysis of in-stent thrombosis by targeting nanoparticles with immobilized tissue plasminogen activator (tPA) to a stented pig coronary artery [24].

The implant-assisted magnetic targeting concept requires that the stents can be magnetized, a prerequisite that often is not compliant with most current commercial stents. The next generation of stents under development includes the biodegradable stents [25]. Stents made of magnetizable corrodible alloys may be advantageous options as they will allow single or repeated targeted (multi)drug delivery during the healing period.

Magnetic drug targeting is a promising therapy that can benefit patients, as well as provide novel opportunities for pharmaceutical and medical technology/device industries. Packaging a proprietary drug into magnetic nanoparticles can provide a drug company with patent protection based on the formulation for continued revenues beyond expiration of the original patent. Owing to the manufacturing complexity and difficulties in demonstrating bioequivalence, generic companies are less likely to develop generic therapeutic nanoparticles [26]. Potent drug candidates that have been abandoned owing to adverse systemic effects can potentially be reconsidered with a magnetically targeted therapy regime. Concentration of the drug at the diseased tissues/cells results in an overall lower dose and reduced systemic toxicity. For the stent device industry, the strategy of implant-assisted magnetic targeting provides opportunities for the development of novel biodegradable stents. Last, the method allows magnet manufacturers the opportunity to develop more products for commercialization and corporate growth.

Financial & competing interests disclosure

Maria Kempe has a Swedish patent on magnetic nanoparticles (SE532436) and has recently submitted another patent application on magnetic nanoparticles with Henrik Kempe. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.