Achieving Localised Delivery With Magnetic Vectoring

Q. What is magnetic vectoring and why is this approach different from other delivery technologies?

The concept of nanomagnetic therapy is based on the unique properties of magnetically responsive nanoparticles (MNP) responding to an applied magnetic field gradient. MNP are nanoscale, ferromagnetic materials that present spontaneous magnetisation in an applied magnetic field, and exhibit rapid demagnetisation with no remanence when the field is removed. This superparamagnetism is, in essence, a magnetic (or biomagnetic as I like to call it) on–off switch that can be exploited in numerous ways to offer enhanced/advanced therapeutic options, ranging from early-stage diagnostics to medical imaging to localised drug delivery.

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The idea of using magnetic forces to enhance treatment therapies and improve therapeutic benefit has been around for many decades, but advances in this area are only now being realised thanks to the emerging field of nanomedicine and the application of nanotools to treatment modalities.

Q. What is the potential for magnetic delivery systems in medical therapies? What progress have pharma companies already made in this area?

Charles E. Seeney

Magnetic-based therapies can be traced back through several centuries and, for the interested, an excellent historical review is presented in Magnetism in Medicine (1). Recent progress, with the development of smaller and more powerful magnets leading to highly functional miniaturised devices, has seen the expansion of magnetic applications across a spectrum of treatment methodologies that are being investigated in the clinic, such as cell separation, magnetic resonance imaging, enhanced gene transfer, localised targeted delivery of therapeutics or magnetically induced hyperthermia and early-stage cancer diagnostics. Recently, magnetic nanoparticles have also been applied to applications in tissue engineering and are being used to construct multilayered cell structures. In addition, applications in areas of allergy diagnosis are under study.

One significant development is magnetically guided catheter technology, which is now used in cardiac stimulation and ablation therapy (2, 3). Although this is considered to be an invasive therapy, it offers the potential for site-specific drug delivery. In cardiac ablation therapy for the treatment of atrial fibrillation, where surgical procedures are indicated, a cardiac interventional workstation is used to navigate a catheter over short distances to the site of the arrhythmia. An extension of this procedure is the delivery of therapeutics to the site as well, being held in place using MNPs.

The advent of functionalised MNP, such as ferromagnetic materials with superparamagnetic properties, has further opened new opportunities within the field of nanomedicine for targeted therapies. Progress in the development of nanomagnetic treatment modalities can generally be described as following two paths; one is based on implanted MNPs, where the oscillation of the particles provides the benefit, while the second path uses MNPs as vehicles or carriers for targeted therapeutics.

Only a limited number of nanoscale therapeutic formulations demonstrating both enhanced solubility and drug targeting properties have received FDA approval (5). To date, however, nanomagnetic therapies have only reached limited clinical use (4). One drug targeting system for doxorubicin using micromagnetic (as opposed to nanoscale) particles, developed in the late 1990s, failed in clinical trials (6). Although presenting much potential, nanoscale biomaterials have been slow to develop into clinical applications. This can be attributed to a variety of reasons. The first is generally related to the physics of nanoparticles and the development of characterisation methods for understanding and preventing behaviour, such as particle interactions and agglomeration in the physiological environment. A second reason relates to methods for defining and understanding the biodistribution and specificity of nanoscale therapeutic formulations, which remains imperfect because of the body's complex response to nanoscale materials. Thirdly, it i difficult to find a delivery methodology for site-specific or organ-specific targeting.

Recent advances in nanomaterial preparation and characterisation indicate that it is possible to overcome these limitations by using MNPs as drug carriers to improve drug localisation and overcoming cytotoxic effects. While magnetic targeting is not likely to be effective in all situations, with further development it should provide another tool for disease treatment.

Although commercial success has been limited so far, the application of nanomagnetics to drug targeting opens a range of new opportunities for enhanced therapeutic performance, as described with magnetic vectoring (7, 8), magnetofection (9), magnetic hyperthermia (10) or with tissue vibration (11). These technologies are all at varying stages of development, but could deliver new therapeutic options for physicians and patients in the coming years.

Q. How is nanotechnology applied to improve magnetic delivery systems? In which medical applications could it potentially be applied?

Magnetic vectoring can be considered as a two-stage process (at least), in which the MNP-drug construct is first caused to magnetically concentrate at a target site, such as a tumour, using externally shaped magnetic field gradients. Following extravasation where the potential for resistance to drug penetration (tumour interstitial fluid pressure) is overcome, the pro-drug is subsequently cleaved within the tumour microenvironment. Ideally, the MNP-drug construct remains nontoxic until cleaved within the tumour matrix. Additional components, such as affinity-based vectors, can be incorporated onto the construct for improved attachment and uptake (4).

Nanoscale devices and carriers exploit the enhanced permeability and retention effect because they are small enough to traverse pores in the inherently disordered tumour vasculature. In addition, the 'nano' effect of increasing the surface area to volume–mass ratio with decreasing size enables high-drug loading on the particle surface. However, this advantage must be balanced with the retention of adequate magnetic susceptibility to enable magnetic deflection to successfully exit the vasculature.

Current magnetic field technology already allows drugs to be applied to tumours at superficial sites (e.g., close to the skin or gliomas just underneath the skull) (4, 7, 8, 12, 13). We also believe that innovation will enable magnetic field gradients to be constructed with the potential to manipulate MNP-drug constructs at visceral sites, such as the pancreas. It is also envisioned that this platform technology, in addition to localised drug delivery, will be able to open and close sphincters, aid hearing amplification and remediation, and promote controlled muscle movement. Using the biomagnetic switch concept, implanted MNPs can be used to drive tissue movement or vibration in response to an oscillating magnetic field (11). This concept can also be applied, for example, to the treatment of gastrointestinal reflux disorder by magnetically opening and closing the muscle, or in driving middle ear vibrations in response to an auditory input, or perhaps moving impaired muscle such as the blinking of eyelids.

Q. When exploring the possibility of nanotechnology in a medical therapy, what are the potential safety concerns? How are safety issues monitored throughout research?

Safety concerns around nanomedicines have had persistently high visibility in the public domain—much more so than other therapeutics without the "nano" label. Concerns are based on the notion that nanoscale materials may distribute into and persist in anatomical compartments in a way that is not typical for other therapeutic agents. However, research activities, including those based on nanotechnology, are governed and monitored by regulators. At some point in the research process, very early on or after concept validation, the development effort will incorporate studies to address both biodistribution and toxicity effects. This early effort sets the stage for determining the potential viability of the methodology as it progresses through subsequent preclinical studies.

Q. What tools, techniques, equipment and expertise are needed to conduct nano-enabled drug research? Given that nanomedicine is a relatively new field of research, how difficult is to find the right skills, experience and equipment?

Nanotechnology is an enabling technology, in which an ultraminiaturised process, procedure or application has the capacity to run better, faster, more efficiently or more effectively. As a nanotool, this concept can apply to technology development across the spectrum of scientific disciplines; thus, achieving a successful result also requires a merger of scientific skills/disciplines. To address this, both government and academic institutions have established various types of nanotechnology R&D centres/clusters for collaborative efforts, so that the range of required technical skills are seated in a single, discrete location. These clusters also house the expensive basic research and characterization tools, such as atomic force microscopy, electron microscopy, x-ray diffraction, and magnetic instrumentation, which can carry research well through concept validation (14, 15).

Scientists who can understand and merge the concepts and principles of nanotechnology with medicine to develop advanced treatments are definitely in short supply. A successful project in nanomedicine that delivers a new drug targeting technology can incorporate many disciplines including nanophysics, magnetic physics, organic/biochemistry, molecular biology and oncology. Finding a team can require a lot of effort.

Q. Several innovative nanomedicine projects are currently being researched and developed. What is needed to push these projects further and accelerate development?

The commercialisation of nanobased products and technologies is still mainly being conducted through start-ups and technology business ventures. These small business units typically take an early-stage technology from a university and, over a period of several years, attempt to acquire an intellectual property position that can attract major investor and development capital. Concurrently, the venture has to develop a feasible path through clinical trials and regulatory clearance. Because of the complex business relationships required, the cost to establish an intellectual-property base, the cost to conduct the fundamental research to get to clinical trials, and the uncertainty of regulatory requirements for nanoscale therapeutics (e.g., is it a device or a therapeutic?), many nanobiotechnology ventures end up in the "Valley of the Shadow", perhaps due to circumstances simply beyond their control.

Realistically, the usual criteria still apply in terms of a securing a new drug application for nanotechnology-based therapeutics. In part, these criteria include the following:

• Can the nanomaterial be produced with batch-to-batch purity and consistency under GMP conditions?

• What particular matters surround the stability and handling of the agent?

• Do the required animal toxicology studies provide an expectation that toxicities in human will be manageable?

In addition, it's important to consider the current situation with regards to patents. In the US, for instance, there is a significant backlog of nanobased patent applications that continues to grow. These added uncertainties, coupled with an inability to deal with them, can lead to extended development times and higher costs before the venture can even acquire the resources to establish a clinical path. In a weak economy, early stage capital becomes virtually impossible to find.

Q. Some have claimed that many Big Pharma companies are losing interest in nanoenabled drugs. Do you agree with this statement?

In many cases, such people are referring to nanoscale-therapeutic formulations, which offer some incremental performance changes through enhanced drug solubility and/or affinity-based targeting. Almost from inception, however, there has been a considerable risk that the benefits of such nano drug formulations may have been too hyped and oversold. True breakthrough drug technologies arising from this approach have yet to materialise. It also worth bearing in mind that virtually all medicines and diagnostic agents previously available to clinicians, prior to the wave of interest in nanotechnology, were already nanoscaled. Nevertheless, the rational design of a new generation of therapeutics is firmly based on increased sophistication that allows for localised delivery via systemic administration, with minimal impact on normal tissue, as well as a growing understanding of tumour biology.

Pharmaceutical interest will certainly increase with the development of treatment methodologies that provide for increased dosage forms, with higher concentrations of drug delivered to the target site.

Charles E. Seeney is Managing Director, ViCorp Tech LLC, and CEO, NanoBioMagnetics. (Edmond, OK USA).

References

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13. M.Y. Hua et al., Biomaterials 32(2), 516–27 (2011).

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