The emerging applications of magnetic nanovectors in nanomedicine.

The scientific disciplines that encompass medical therapy and diagnostics, in a continuing transition to personalized medicine, have found a valuable tool in the emerging field of nanotechnology. New nanotools are now enabling discoveries and advancements that form the foundation of what has become known collectively as nanomedicine. The global impact of these advancements are being seen in areas of advanced/improved early stage diagnostics, targeted drug delivery systems and imaging methods, all leading to more effective diagnostic/therapeutic strategies and outcomes. This review focuses on recent patent advancements in this transition with emphasis on the emerging role of magnetic nanovectors as enabling tools for the enhanced effectiveness of cancer diagnostics and therapeutics, considering its historical progression and future impact.

Magnetic nanovectors for drug delivery.

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.

Magnetic nanovectors for drug delivery.

Nanotechnology holds the promise of novel and more effective treatments for vexing human health issues. Among these are the use of nanoparticle platforms for site-specific delivery of therapeutics to tumors, both by passive and active mechanisms; the latter includes magnetic vectoring of magnetically responsive nanoparticles (MNP) that are functionalized to carry a drug payload that is released at the tumor. The conceptual basis, which actually dates back a number of decades, resides in physical (magnetic) enhancement, with magnetic field gradients aligned non-parallel to the direction of flow in the tumor vasculature, of existing passive mechanisms for extravasation and accumulation of MNP in the tumor interstitial fluid, followed by MNP internalization. In this review, we will assess the most recent developments and current status of this approach, considering MNP that are composed of one or more of the three elements that are ferromagnetic at physiological temperature: nickel, cobalt and iron. The effects on cellular functions in vitro, the ability to successfully vector the platform in vivo, the anti-tumor effects of such localized nano-vectors, and any associated toxicities for these MNP will be presented. The merits and shortcomings of nanomaterials made of each of the three elements will be highlighted, and a roadmap for moving this long-established approach forward to clinical evaluation will be put forth.

Magnetically vectored platforms for the targeted delivery of therapeutics to tumors: history and current status.

Superparamagnetic iron oxide nanoparticles (SPIONs) are being developed as vehicles for the selective targeting of therapeutics and bioactive compounds. Presented herein is a brief review of the history of approaches to magnetic-based drug delivery platforms, leading to current concepts of magnetically vectored therapeutics via functionalized SPION-prodrugs. With this background, recent experimental results are discussed that demonstrate the use of shaped external magnetic field gradients, generated by designed configurations of permanent magnets, to drive the concentration/accumulation of modified SPION-prodrug constructs at a tumor site, followed by tumor extravasation and activation of the prodrug within the tumor microenvironment. In order to successfully translate this approach to clinical application, one of the key requirements is the ability to magnetically drive ('vector') the SPION to human-scale tumor settings. In this review, various configurations of permanent magnets are described and models are presented that demonstrate that magnetic field gradients can potentially be focused and extended to lengths of several inches in vivo. This modification thereby increases the range of the delivery platform, and offers the potential for the treatment of visceral as well as superficial tumors and for translation from preclinical animal tumor models to clinical settings. The methodology of magnetically vectored prodrug therapeutics, as a means for selective localized targeting of tumor tissue, and minimizing harm to normal tissue, has the additional advantage of raising the therapeutic index compared with that of free drugs, thus, offering great potential as a cancer treatment modality.

Molecular magnetic resonance imaging approaches used to aid in the understanding of angiogenesis in vivo: implications for tissue engineering.

In tissue engineering it is often necessary to assess angiogenesis associated with engineered tissue grafts. The levels of vascular endothelial growth factor receptor 2 (VEGF-R2) is elevated during angiogenesis. The goal of this study was to develop and assess a novel magnetic resonance imaging (MRI) molecular probe for the in vivo detection of VEGF-R2 in an experimental rodent model of disease. The possible use of the probe in tissue engineering applications is discussed. The molecular targeting agent we used in our study incorporated a magnetite-based dextran-coated nanoparticle backbone covalently bound to an anti-VEGF-R2 antibody. We used molecular MRI with an anti-VEGF-R2 probe to detect in vivo VEGF-R2 levels as a molecular marker for gliomas (primary brain tumors). Tumor regions were compared with normal tissue. Nonimmune nonspecific normal rat immunoglobulin G coupled to the dextran-coated nanoparticles was used as a control. Prussian blue staining for iron-based nanoprobes was used to confirm the specificity of the probe for VEGF-R2 in glioma tissue. VEGF-R2 levels in tumor tissues were also confirmed in western blots and via immunohistochemistry. Based on our results, in vivo evaluation of tissue angiogenesis using molecular MRI is possible in tissue engineering applications.

Epithelial internalization of superparamagnetic nanoparticles and response to external magnetic field.

Superparamagnetic magnetite nanoparticles (MNP) coated with silica were synthesized and chronically implanted into the middle ear epithelial tissues of a guinea pig model (n=16) for the generation of force by an external magnetic field. In vivo limitations of biocompatibility include particle morphology, size distribution, composition and mode of internalization. Synthesis of MNP was performed using a modified precipitation technique and they were characterized by transmission electron microscopy, X-ray diffractometry and energy dispersive spectroscopy, which verified size distribution, composition and silica encapsulation. The mechanism for internalizing 16+/-2.3 nm diameter MNP was likely endocytosis, enhanced by magnetically force. Using sterile technique, middle ear epithelia of tympanic membrane or ossicles was exposed and a suspension of particles with fluoroscein isothiocyanate (FITC) label applied to the surface. A rare earth, NdFeBo magnet (0.35 T) placed under the animal, was used to pull the MNP into the tissue. After 8 days, following euthanasia, tissues were harvested and confocal scanning laser interferometry was used to verify intracellular MNP. Displacements of the osscicular chain in response to an external sinusoidal electromagnetic field were also measured using laser Doppler interferometry. We showed for the first time a physiologically relevant, biomechanical function, produced by MNP responding to a magnetic field.