Role of nanotechnology in developing new therapies for diseases of the nervous system

“Despite all the advances in neurology...there are serious deficiencies in our understanding of the pathomechanism of several neurological disorders, as well as our ability to diagnose and treat these disorders.”

Nanobiotechnologies that are currently under investigation in the life sciences, pharmaceuticals and diagnostics will soon find applications in the practice of medicine [1]. This area is referred to as nanomedicine, which is not a branch or specialty in medicine as such, but simply implies improvement of diagnosis as well as therapy based on nanotechnology. Diseases of the nervous system are an important part of medicine. Despite all the advances in neurology, particularly in the last decade of the 20th century (‘decade of the brain’), there are serious deficiencies in our understanding of the pathomechanism of several neurological disorders, as well as our ability to diagnose and treat these disorders. Examples of how nanobiotechnology will impact neurology are shown in Box 1.

Role of nanobiotechnology in neurodiagnosis

Refinements in the noninvasive diagnosis of neurological disorders are important because direct access to the CNS is difficult. Nanobiotechnology has refined molecular diagnostics in general, including applications to CNS disorders, such as infections and tumors of the brain. Nanotechnology ‘on a chip’ is a new paradigm for total chemical analysis systems on a nanoscale. The most practically useful and initial applications are expected in point-of-care diagnostics, in which nanotechnology provides advantages over conventional nucleic acid-based chips; this will also improve the diagnosis of CNS disorders.

Nanobiotechnology has refined brain imaging. Ultra-small superparamagnetic iron oxide (USPIO) is a cell-specific contrast agent for MRI. An open-label Phase II study has tested the potential of USPIO-enhanced MRI for macrophage imaging in human ischemic lesions [2]. USPIO-induced signal alterations throughout differed from signatures of conventional gadolinium-enhanced MRI, thus being independent from a breakdown of the blood–brain barrier (BBB). Macrophages, as the prevailing inflammatory cell population in stroke, contribute to brain damage. USPIO-enhanced MRI may provide an in vivo surrogate marker of cellular inflammation in stroke and other CNS pathologies.

Nanowires for monitoring brain activity

Electrical recording from the spinal cord vascular capillary bed has been achieved, demonstrating that the intravascular space may be used as a means to address brain activity without violating the brain parenchyma. Working with platinum nanowires and using blood vessels as conduits to guide the wires, researchers have successfully detected the activity of individual neurons lying adjacent to the blood vessels [3]. This can provide an understanding of the brain at the neuron–neuron interaction level with nonintrusive, biocompatible and biodegradable nanoprobes. This technique may one day enable monitoring of individual brain cells and perhaps provide new treatments for neurological diseases. Because the nanowires can deliver electrical impulses as well as receive them, the technique has the potential as a treatment for Parkinson’s disease (PD). It has already been shown that patients with PD can experience significant improvement from direct stimulation of the affected area of the brain. However, the stimulation is currently carried out by inserting wires through the skull and into the brain, a process that can cause scarring of the brain tissue. By stimulating the brain with nanowires threaded through blood vessels, patients can receive the benefits of treatment without the damaging side effects. The challenge is to guide the nanowire probes precisely to a predetermined spot through the thousands of branches in the brain’s vascular system. One solution is to replace the platinum nanowires with new conducting polymer nanowires. Not only do the polymers conduct electrical impulses, they change shape in response to electrical fields, which would allow the researchers to steer the nanowires through the brain’s circulatory system. Polymer nanowires have the added benefit of being 20–30-times smaller than the platinum ones used in the reported laboratory experiments. They are biodegradable and therefore suitable for short-term brain implants.

Application of nanotechnology to neuroprotection

Applied nanobiotechnology, aimed at the regeneration and neuroprotection of the CNS, will significantly benefit from basic nanotechnology research conducted in parallel with advances in cell biology, neurophysiology and neuropathology [4]. The ultimate goal is to develop novel technologies that directly or indirectly aid in providing neuroprotection and/or a permissive environment and active signaling cues for guided axon growth. Research at the Silva Research Group for Cellular Neural Engineering of the University of California (San Diego, CA, USA) focuses on using nanotechnologies to study neuropathological processes. The aim is to help neuroscientists better understand the physiology of and develop treatments for disorders, such as brain injury, spinal cord injury, degenerative retinal disorders and Alzheimer’s disease. One of the areas of research in this laboratory is neuroprotection. Quantum dot (QD) technology is used to gather information about how the CNS environment becomes inhospitable to neuronal regeneration following injury or degenerative events by studying the process of reactive gliosis. Glial cells, housekeeping cells for neurons, have their own communication mechanisms that can be triggered to become reactive following injury. QDs are being used to build data-capture devices that are easy to use by neuroscientists and a new protocol has been developed for tracking glial activity. Other research is looking at how QDs might spur the growth of neurites by adding bioactive molecules to the QDs in such a way that a medium that will encourage this growth in a directed fashion is provided.

Improvement of drug delivery to the CNS

Delivery of drugs to the CNS is a challenge. Currently, most of the strategies are directed at overcoming the BBB, which represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents and a variety of CNS-active drugs, especially neuropeptides. One of the possibilities for overcoming this barrier is drug delivery to the brain using nanoparticles. Drugs that have been transported successfully into the brain using this carrier include the hexapeptide dalargin, the dipeptide kytorphin, loperamide, tubocurarine and doxorubicin. The mechanism of the nanoparticle-mediated transport of the drugs across the BBB is not fully elucidated at present. The most probable mechanism is endocytosis by the endothelial cells lining the brain blood capillaries. The use of nanoparticles to deliver drugs to the brain across the BBB may provide a significant advantage over current strategies. The primary advantage of nanoparticle carrier technology is that nanoparticles mask the BBB-limiting characteristics of the therapeutic drug molecule. Furthermore, this system may slow drug release in the brain, decreasing peripheral toxicity. Currently, reports evaluating nanoparticles for brain delivery have studied anesthetic and chemotherapeutic agents. Nanoparticle technology appears to have significant promise in delivering therapeutic molecules across the BBB [1].

‘The use of nanoparticles to deliver drugs to the brain across the BBB may provide a significant advantage over current strategies’.

Nanofiber brain implants

Several brain probes and implants are used in neurosurgery. Examples are those for the management of epilepsy, movement disorders and pain. Many of these implants are still investigational. The ideal inert material for such implants has not yet been discovered. Silicon probes are commonly used for the recording of electrical impulses and brain stimulation. The body generally regards these materials as foreign and the probes become encapsulated with glial scar tissue, which prevents them from making good contact with the brain tissue.

‘Nanotubules...hold great promise for replacing conventional silicon implants’.

Scientists at Purdue University (IN, USA) have conducted an in vitro study to determine cytocompatibility properties of formulations containing carbon nanofibers pertinent to neural implant applications [5]. Substrates were prepared from four different types of carbon fibers, two with nanoscale diameters (nanophase or ≤100 nm) and two with conventional diameters (>100 nm). Within these two categories, both a high and a low surface energy fiber was investigated and tested. Astrocytes (glial scar tissue-forming cells) were seeded onto the substrates for adhesion, proliferation and long-term function studies (such as total intracellular protein and alkaline phosphatase activity). Results provided the first evidence that astrocytes preferentially adhered and proliferated on carbon fibers that had the largest diameter and the lowest surface energy. Formulations containing carbon fibers in the nanometer regime limited astrocyte functions, leading to decreased glial scar tissue formation. Positive interactions with neurons and, at the same time, limited astrocyte functions leading to decreased gliotic scar tissue formation, are essential for increased neuronal implant efficacy. Nanotubes, because of their interesting electronic properties and reduction in scar formation, hold great promise for replacing conventional silicon implants.

Nanoscaffolds for the repair of neural tissues

There are several barriers that must be overcome to achieve axonal regeneration after injury in the CNS: scar tissue formation; gaps in nervous tissue formed during phagocytosis of dying cells after injury; factors that inhibit axon growth in the mature mammalian CNS; and failure of many adult neurons to initiate axonal extension.

Using the mammalian visual system as a model, a self-assembling peptide nanofiber scaffold was designed, which creates a permissive environment for axons not only to regenerate through the site of an acute injury but also to knit the brain tissue together. In experiments using a severed optic tract in the hamster, regenerated axons reconnected to target tissues with sufficient density to promote the functional return of vision, as evidenced by visually elicited orienting behavior [6]. The peptide nanofiber scaffold not only represents a previously undiscovered nanobiomedical technology for tissue repair and restoration but also raises the possibility of effective treatment of CNS and other tissue or organ trauma. This peptide nanofiber scaffold has several advantages over currently available polymer biomaterials: it forms a network of nanofibers that are similar in scale to the native extracellular matrix and therefore provides an ‘in vivo’ environment for cell growth, migration and differentiation; it can be broken down into natural l-amino acids and metabolized by the surrounding tissue; it is synthetic and free of chemical and biological contaminants that may be present in animal-derived biomaterials, such as collagens; and it appears to be immunologically inert, thus avoiding the problem of neural tissue rejection.

Nanoparticles as an aid to neurosurgery

A research team from Oregon Health & Science University (OR, USA) has shown that an iron oxide nanoparticle can outline not only brain tumors under MRI but also other lesions in the brain that may otherwise have gone unnoticed [7]. Ferumoxtran-10 (Combidex®, Advanced Magnetics Inc.), a dextran-coated iron oxide nanoparticle, provides enhancement of intracranial tumors by MRI for more than 24 h and can be imaged histologically by iron staining. Each iron oxide nanoparticle is the size of a small virus and is much smaller than a bacterium but is much larger than an atom or standard gadolinium-contrast molecule. It is an iron oxide crystal surrounded by a carbohydrate or ‘sugar’ coating called dextran that gives the particle a longer plasma half-life, allowing it to slowly slip through the BBB, a natural defense system that blocks the entry of foreign substances, including therapeutic agents.

This research team also found that ferumoxtran-10 provides a stable imaging marker during surgery to remove brain tumors and it remains in the brain long enough for post-operative MRI, even after surgical manipulation. These findings have the potential to assist image-guided brain surgery and improve the diagnosis of lesions caused by multiple sclerosis, stroke and other neurological disorders, in addition to residual tumors. This is one of the first biologically specific nanoparticles to be used in clinical trials. Because ferumoxtran-10 can stay in brain lesions for days, it can be administered to patients 24 h before surgery and can image other, noncancerous lesions. It has some advantages over gadolinium, a metal used as a magnetic resonance contrast agent for 20 years and which must be administered just before surgery. However, it will complement gadolinium, but not replace it. Ferumoxtran-10 gives additional information that cannot be obtained in some patients with gadolinium. Using both the contrast agents, one can get better diagnostic information and that has the potential to improve the patient’s outcome. In addition, ferumoxtran-10 can be detected with an iron stain in the tissue removed by biopsy or surgery, allowing physicians to see it in brain tissue samples under a microscope. Unlike any other MRI contrast agent, ferumoxtran-10 enables the comparison of images from a MRI scan with the tissue taken out at surgery. Moreover, it is relatively safe when diluted and administered as an infusion.

Concluding remarks

Refinements in nanobiotechnologies, as applied to the nervous system, will improve our understanding of neurological disorders and drug development as well as drug delivery for CNS disorders. Improvement of diagnostics by nanotechnology, as mentioned earlier, has a positive impact on personalized medicine as well as neurology. The personalized approach will also further improve the management of neurological disorders [8].