Cancer therapy with iron oxide nanoparticles: Agents of thermal and immune therapies

Abstract

Significant research and preclinical investment in cancer nanomedicine has produced several products, which have improved cancer care. Nevertheless, there exists a perception that cancer nanomedicine 'has not lived up to its promise' because the number of approved products and their clinical performance are modest. Many of these analyses do not consider the long clinical history and many clinical products developed from iron oxide nanoparticles. Iron oxide nanoparticles have enjoyed clinical use for about nine decades demonstrating safety, and considerable clinical utility and versatility. FDA-approved applications of iron oxide nanoparticles include cancer diagnosis, cancer hyperthermia therapy, and iron deficiency anemia. For cancer nanomedicine, this wealth of clinical experience is invaluable to provide key lessons and highlight pitfalls in the pursuit of nanotechnology-based cancer therapeutics. We review the clinical experience with systemic liposomal drug delivery and parenteral therapy of iron deficiency anemia (IDA) with iron oxide nanoparticles. We note that the clinical success of injectable iron exploits the inherent interaction between nanoparticles and the (innate) immune system, which designers of liposomal drug delivery seek to avoid. Magnetic fluid hyperthermia, a cancer therapy that harnesses magnetic hysteresis heating is approved for treating humans only with iron oxide nanoparticles. Despite its successful demonstration to enhance overall survival in clinical trials, this nanotechnology-based thermal medicine struggles to establish a clinical presence. We review the physical and biological attributes of this approach, and suggest reasons for barriers to its acceptance. Finally, despite the extensive clinical experience with iron oxide nanoparticles new and exciting research points to surprising immune-modulating potential. Recent data demonstrate the interactions between immune cells and iron oxide nanoparticles can induce anti-tumor immune responses. These present new and exciting opportunities to explore additional applications with this venerable technology. Clinical applications of iron oxide nanoparticles present poignant case studies of the opportunities, complexities, and challenges in cancer nanomedicine. They also illustrate the need for revised paradigms and multidisciplinary approaches to develop and translate nanomedicines into clinical cancer care.

Keywords: Cancer; Immune therapy; Iron deficiency anemia; Iron oxide nanoparticles; Magnetic nanoparticle hyperthermia; Nanomedicine.

Figure 1:. Schematic illustration of the magnetic nanoparticle hyperthermia concept.

Magnetic nanoparticles comprising a magnetic core and a biocompatible coating suspended in liquid are directly injected into a liver tumor. An alternating magnetic field applicator generates an alternating magnetic field that interacts with the magnetic nanoparticles, generating local heat.

Figure 2:. Schematic ol magnetic Hysteresis ana heating by torced hysteisis in an alternating magnetic field.

(Left) A diagram of an idealized hysteresis loop showing the characteristic parameters (M_S, M_R, H_C, and H_sat) relevant for heat generation for magnetic hyperthermia. (Right) Illustration of the microscopic origin of the global field-dependent magnetization. M(H), of an idealized ensemble of non-interacting (single-domain) magnets (nanoparticle), some of which contain a representative cartoon of M(H) highlighting that the hysteresis loop of each panicle may significantly differ from that of other magnets. Differences depicted here arise from the relative orientations of each magnet’s moment (M) about its easy-axis orientation (represented by the yellow lines within each particle). Also depicted are the single-particle characteristic switching field (H_S). which does not apply to the left average loop. The red vertical branches illustrate that heat is only dissipated on those irreversible portions.