Current Medicinal Chemistry - Volume 21, Issue 37, 2014

The current rapid development of nanotechnologies and engineered nanomaterials (ENM) will impact the society in a major fashion during the coming decades. This development also causes substantial safety concerns. Among the many promising applications of ENM, products that can be used for diagnosis and treatment of diseases, including conditions that affect the nervous system, are under development. ENM can pass the blood brain barrier (BBB) and accumulate within the brain. It seems that the nano-form rather than the bulk form of the chemicals pass the BBB, and that there is an inverse relationship between particle size and the ability to penetrate the BBB. Although translocation of ENM to the brain is possible during experimental conditions, the health relevance for real-life situations is far from clear. One major reason for this is that studies have been using nanoparticle concentrations that are far higher than the ones that can be expected during realistic exposures. However, very high exposure to the CNS can cause effects on neurotransmission, redox homeostasis and behavior. Available studies have been focusing on possible effects of the first generation of ENM. It will be necessary to study possible health effects also of expected novel sophisticated materials, independent of the outcome of present studies. The prospects for intended or targeted medical applications are promising since it has been shown that ENM can be made to pass the BBB and reach specific regions or cells within the brain.

Nanomedicine, an emerging therapeutic tool in current medical frontiers, offers targeted drug delivery for many neurodegenerative disorders. Neuroinflammation, a hallmark of many neurodegenerative disorders, is mediated by microglia, the resident immunocompetent cells of the central nervous system (CNS). Microglial cells respond to various stimuli in the CNS resulting in their activation which may have a beneficial or a detrimental effect. In general, the activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, chemokines and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Hence, controlling microglial inflammatory response and their proliferation has been considered as an important aspect in treating neurodegenerative disorders. Regulatory factors that control microglial activation and proliferation also play an important role in microglia-mediated neuroinflammation and neurotoxicity. Various anti-inflammatory drugs and herbal compounds have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing blood brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps and several other factors prevent the entry of these drugs into the CNS. Use of non-degradable delivery systems and microglial activation in response to the drug delivery system further complicate drug delivery to the CNS. Nanomedicine, a nanoparticle-mediated drug delivery system, exhibits immense potential to overcome these hurdles in drug delivery to the CNS enabling new alternatives with significant promises in revolutionising the field of neurodegenerative disease therapy. This review attempts to summarise various regulatory factors in microglia, existing therapeutic strategies in controlling microglial activation, and how nanotechnology can serve to improve the delivery of therapeutic drugs across the BBB for treating microglia- mediated neuroinflammation and neurodegeneration.

Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymerdrug conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these Np seems to have been exceeded by targeted liposomes, a platform based on a proven technology. This drug delivery system entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A key issue is that it is virtually impossible to define the in vivo fate of polymers, especially in the brain, which is a regulatory requirement; perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumours are emerging, such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The success or failure in the approval of the polymeric Np currently in clinical trials will certainly affect the field. At present, the chances of their approval appear to be very low.

Many potential drugs for the treatment of neurological diseases are unable to reach the brain in sufficient enough concentrations to be therapeutic because of the blood brain barrier. On the other hand, direct delivery of drugs to the brain provides the possibility of a greater therapeutic-toxic ratio than with systemic drug delivery. The use of intranasal delivery of therapeutic agents to the brain provides a means of bypassing the blood brain barrier in a non-invasive manner. In this respect, nanosized drug carriers were shown to enhance the delivery of drugs to CNS compared to equivalent drug solution formulations. Neurological conditions that have been studied in animal models that could benefit from nose-to-brain delivery of nanotherapeutics include pain, epilepsy, neurodegenerative disease and infectious diseases. The delivery of drugs to the brain via the nose-to-brain route holds great promise, on the basis of preclinical research by means of drug delivery systems such as polymeric nanoparticles and clinical data related to intranasal delivery to CNS of large molecular weight biologics administered in solution, but safety issues about toxicity on nasal mucosa, Np transport into the brain, delivery only to specific brain regions and variability in the adsorbed dose still represent research topics that need to be considered, with a view of clinical translation of these delivery systems.

Chondroitin sulfate proteoglycans (CSPGs) are complex biomolecules that are known to facilitate patterning of axonal direction and cell migration during the early growth and development phase of the mammalian central nervous system (CNS). In adults, they continue to control neuronal plasticity as major constituents of the “peri-neuronal nets” (PNNs) that surround adult CNS neurons. CSPGs are also barrier-forming molecules that are selectively upregulated by invading reactive astroglia after injury to the CNS, and are responsible for the active repulsion of regenerating neurons post-injury. Recent evidence however suggests that the diverse sulfated glycosaminoglycan (GAG) side chains attached to CSPGs are key components that play paradoxical roles in influencing nerve regeneration post-injury to the CNS. Sulfated GAG repeats attached to the CSPG core protein help mediate cell migration, neuritogenesis, axonal pathfinding, and axonal repulsion by directly trapping and presenting a whole host of growth factors to cells locally, or by binding to specific membrane bound proteins on the cell surface to influence cellular function. In this review, we will present the current gamut of interventional strategies used to bridge CNS deficits, and discuss the potential advantages of using sulfated GAG based biomaterials to facilitate the repair and regeneration of the injured CNS.

Spinal cord injury (SCI) is a common neurologic disorder that results in loss of sensory function and mobility. It is well documented that tissue engineering is a potential therapeutic strategy for treatment of SCI. In this connection, various biomaterials have been explored to meet the needs of SCI tissue engineering and these include natural materials, synthetic biodegradable polymers and synthetic non- degradable polymers. Nanofiber scaffolds are newly emerging biomaterials that have been widely utilized in tissue engineering recently. In comparison to the traditional biomaterials, nanofibers have advantages in topography and porosity, thus mimicking the naturally occurring extracellular matrix. Besides, they exhibit excellent biocompatibility with low immunogenicity, and furthermore they are endowed with properties that help to bridge the lesion cavity or gap, and serve as an effective delivery system for graft cells or therapeutic drugs. This review summarizes some of the unique properties of nanofiber scaffolds which are critical to their potential application in treatment of injured spinal cord.

Stroke or cerebral vascular accidents are among the leading causes of death in the world. With the availability of Digital Subtraction Angiography, transluminal angioplasty has become feasible in many situations and the role of intracranial stents is becoming ever more important in the management of cerebral vascular diseases. In current review, we outline the chronological development of various stents namely; balloon expandable stent, self-expandable open cell stent, self-expandable close cell stent and the flow diverting stent. Further we discuss their advantages and limitations in terms of stent migration, thromboemboli, damage to vessels during procedure, in-stent stenosis and hyper-perfusion damage. We also discuss the importance of in-situ endothelialization, controlled expandability and hemodynamic manipulation in stent design. Further, we summarized the role and need for further development in the areas of bio-compatible materials, endothelial progenitor cell capture technique, bio-functionalized-magnetic-nano-particles and nanotechnology which are significant in intracranial stent development.

Intracranial aneurysms are present in 1-5% of population and can be described as “ticking time bombs” that can go off at any time and cause serious harms including permanent disability and death. There are two routinely practiced treatment options for this disease; endovascular coiling and surgical clipping. In recent years other promising methods, such as stent-assisted coiling, flow diverting devices and Onyx embolic agent, have also been developed and tested. The studies reviewed here suggest endovascular coiling to be the most commonly chosen treatment method and that there are reservations on using the newly developed techniques, despite studies suggesting their safety and effectiveness. Therefore, it is now becoming clear that a competent management system, in which treatment methods are chosen to best fit the characterisation of the patient and the aneurysm, should be developed in order to effectively diagnose and treat intracranial aneurysms. One way to develop such a system could be through the advancements of nanotechnology and smart materials. Neurosurgery, like many other areas of the medical field, is moving towards adopting the exciting and rapidly developing technologies based on nanomaterials as the nano-approach to detect and treat intracranial aneurysms could offer surgical opportunities that were more invasive or out of rich at the microneurosurgery level.