Magnetic Nanoparticle-based Approaches to Locally Target Therapy and Enhance Tissue Regeneration in vivo

Conclusion & Future Perspective

Magnetic-based systems utilizing superparamagnetic nanoparticles and various configurations of magnetic fields and field gradients provide a range of new opportunities for a number of clinical applications. For certain medical conditions, localized therapy is highly desirable as it can enable administration of a significantly lower drug dose, thus minimizing systemic drug-induced toxicity. Magnetically mediated localization of therapeutic agents (e.g., drugs, genes and cells) is a promising approach to improve the efficacy and safety of the administered therapy resulting in improved clinical outcomes. Furthermore, magnetic targeting can enable redosing or administration of an additional drug at the diseased site, which for example, is highly desirable for treatment of vascular lesions where metallic stents are currently used to alleviate re-obstruction of the blood vessels.

Although promising results have been achieved demonstrating the potential of magnetic targeting, many challenges still exist in order to successfully translate this technology into clinical settings. Substantial improvements in both the magnetic carriers and the targeting magnet systems are likely to be necessary to make the magnetic targeting a viable clinical treatment modality. A number of applications, such as drug delivery to brain tumors, the inner ear and stented blood vessels, which require penetration of a cellular barrier (e.g., BBB, RWM and endothelial luminal layer underlying the walls of blood vessels). The overall objectives of drug targeting consist not only in physical guidance, but also in the retention of the therapeutic agent at the target site. The retention of therapy could be achieved by the magnetically facilitated transport of magnetic carriers through the tissue, overcoming the cellular barriers mentioned above. Efficient tissue penetration of therapeutic carriers could also result in a more pharmacologically optimal drug distribution within target tissue improving the therapeutic outcome. Use of a time-varying uniform magnetic field overlaid with the static gradient field has been shown to radically improve transport of magnetic carriers in gels.^[48] This approach can be implemented in real tissues to retain and distribute magnetic drug carriers. Additional strategies that can change the effective resistance of biological tissues and improve drug carrier tissue penetration include use of magnetic carriers with a proteolytic surface to increase the carrier's mobility through the extracellular matrix^[43] or utilization of ultrasound to generate inertial cavitation to improve transdermal drug delivery.^[130,131] A better understanding of these mechanisms will enable the development of means by which distribution of MNPs in soft tissues can be controlled to a significant extent in a number of clinical strategies, radically improving therapeutic outcomes.

Scaling up the magnetic drug delivery technology from animals and laboratory models to humans would probably require the design of magnet systems enabling the pushing of a magnetic carrier inward in contrast to a conventional pulling of carriers, usually achieved using permanent magnets. The need to develop such carrier pushing-magnet systems has been recognized and work is ongoing in this direction.^[23]

Besides the aspects of magnet system design, it is important to realize that there are many challenges related to the nanoparticle–biomolecule interface when magnetic carriers are administered systemically. This phenomenon is termed as the 'protein (biomolecule) corona' and is related to the formation of a protein layer on the surface of nanoparticles, the so called 'bio–nano' interface that the cell actually 'sees' when it interacts with particles.^[132] This biomolecule corona can mask targeting ligands anchored at the particle surface, influence biodistribution in vivo, and affect cell internalization and intracellular trafficking. Considering the implications of the biomolecule corona effect for MNP targeting, there are two possible approaches that can be taken regarding nanoparticle design. One approach is related to surface engineering and would suggest designing an MNP interface that will experience minimal interactions with the surrounding biological environment except for displaying the specific affinity/targeting desired (i.e., a type of adsorption-proof nanoparticle). A second approach would involve exploitation of the 'corona' layer itself for targeting, through understanding which biomolecules promote the delivery of particles to which location.^[133]

The manipulation and control of cells and cellular structures through MNP-based actuation is a relatively new strategy that has shown great potential for tissue engineering and regenerative medicine applications. Magnetically responsive composite scaffolds are very promising materials for these fields as they can enable control of the spatial distribution and temporal kinetics of GF release. They also can enable local control over the induction of tissue regeneration, as opposed to the effect of a diffusible GF, and will provide the first capability to control precisely where proliferation, maturation or differentiation occurs in an engineered tissue. In the future, this positional control of cellular behavior may facilitate the production of tissues composed of multiple cell lineages derived from a single stem cell type.

In summary, we believe that the use of MNPs has great potential for clinical applications. It is also clear that more animal and clinical studies are necessary to fully realize the clinical potential of these magnetic-based systems. Successful translation of this technology to the clinic will require the joint efforts of researchers from multiple disciplinary backgrounds.

Nanomedicine. 2012;7(9):1425-1442. © 2012  Future Medicine Ltd.