ReviewNanotechnology for neurodegenerative disorders
Introduction
Neurodegenerative disorders (ND) are characterized by the progressive loss of structure or function of neurons, often associated with neuronal death. Alzheimer's (AD), Parkinson's (PD), prion (PrD) disease and amyotrophic lateral sclerosis (ALS) are just some examples.
A number of ND have been deeply investigated but, in spite of many progresses, successful early diagnosis and treatment strategies are still limited. One of the main obstacles is the presence of the blood–brain barrier (BBB), which prevents the penetration of the majority of drugs and imaging agents, causing peripheral side-effects. The current possibilities for imaging and therapy of diseases affecting the brain often depends on vascular lesions and leakiness of the BBB [1]. Nanotechnology, which employs engineered materials or devices on a scale between 1 and 100 billionth of a meter (1–100 nm) represents an innovative and promising approach [2]. Currently, several types of NM (nanofibres, nanotubes, nanoparticles, nanogels) are available for biomedical use with different physico-chemical features and applications (Fig. 1).
What renders engineered nanomaterials (NM) attractive, in particular in the biomedical field, is their versatility. In fact, their physical properties may be exploited for diagnosis and/or therapy and also for tissue engineering and regeneration, whereas chemical functionalization may confer them targeting specificity (Fig. 2). In particular, NM may cross the BBB themselves [2] or may be functionalized to enhance the entrance of drugs and/or contrast agents into the brain. Moreover, NM present additional positive features such as high chemical and biological stability, feasibility of incorporating both hydrophilic and hydrophobic molecules, and the possibility to be administered by a variety of routes (including oral, inhalational and parenteral).
This review focuses on the state-of-the-art of current applications of NM in the therapy and diagnosis of the most common ND, highlighting the future nanotechnological approaches.
Section snippets
Nanotechnology to cross the BBB
The BBB is a dynamic physical and biological barrier between blood circulation and the central nervous system (CNS) (Fig. 3). The functional complexity of the BBB is attributed mainly to brain capillary endothelial cells, which restrict the trans-cellular passage, and to intricate tight and adherents junctions between cells, that restrict the para-cellular flux [3].
Different approaches have been tried to overcome the BBB, ranging from invasive techniques, to chemical modifications of drugs and
Nanotechnology for AD
AD is a progressive ND characterized by memory and cognitive dysfunction, that currently affects more than 24 million people worldwide. The neuropathological hallmarks of AD are neurofibrillary tangles consisting of intraneuronal paired helical filaments of hyperphosphorylated tau protein and extracellular plaques composed of β amyloid peptide (Aβ), a 39–43 amino acids fragment of APP (Amyloid Precursor Protein). Small aggregates of Aβ (ADDLs, amyloid-β-derived diffusible ligands) are currently
Nanotechnology for Parkinson's disease
PD is a progressive neurological condition affecting 1–2% of the population over the age of 65, marked by loss of dopaminergic neurons in the substantia nigra, causing difficulties in the control of movements. The pathological hallmark in the brain of PD patients are cytoplasmic inclusions called Lewy's bodies, composed by 50–700 nm long filaments of the protein α-synuclein. Many cellular mechanisms are thought to be involved in neuronal death in PD, such as ER stress, proteasomal and
Nanotechnology for prion disease
PrD are a family of transmissible neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the prion protein (PrP). Creutzfeldt-Jakob disease, the first prion disease identified in man, occurs sporadically with a frequency of about one case per million individuals/year. PrP exists in the ‘healthy’ cellular isoform (PrPC), with two large alpha-helix structures, and the pathogenic, protease-resistant isoform (PrPSc), predominantly β-sheet, that may form toxic amyloid
Nanotechnology for amyotrophic lateral sclerosis
ALS is a fatal ND affecting 1-2/10,0000 person-year. The hallmark of the disease is the selective death of motor neurons in the brain and spinal cord, leading to paralysis of voluntary muscles. Approximately 20% of familial ALS cases are caused by mutations in SOD1 gene, encoding superoxide dismutase enzyme. Mutated SOD1 generates toxic free radicals. Additionally, mutant SOD1 forms intracellular deposits that inhibit chaperone and/or proteasome activity, with subsequent misfolding and
Neuroprotection
CNS injuries are often accompanied by an increased level of reactive oxygen species. Fullerenes have been suggested as radical “sponges” able to incorporate multiple radicals per molecule, thanks to a delocalized π double bond system, and able to remove superoxide radicals through a dismutation catalytic mechanism [43]. A study [44] showed the ability of a tris-malonic acid derivative of the fullerene C60 molecule (C3) to increase the life span of mice lacking mitochondrial superoxide dismutase
Neurotoxicity of NM
While there is a growing interest on the application of NM in biomedical field, little is known about their potential hazard for human health, in particular their possible toxic effects on CNS. [6], [7], [36].
Most of the data in the literature demonstrated that the toxicity of NM depends on many factors including chemical composition, size, shape, surface area, surface charge, and others.
Recently, the effect of surface chemistry (bare, NH2 or COOH functionalized) on the neurotoxicity of SPIONs
Perspectives and conclusion
Scientists are unraveling molecular, cellular and circuit functions of the nervous system and are identifying genes and pathways that cause neurodegeneration. In the last years, revolutionary progresses resulted from the development of nanotechnology, opening the way for a nano-based therapy and diagnosis of ND. However, more investigation will be necessary in this field to allow the translation from preclinical to concrete clinical applications.
An intriguing challenge will be the use of NM for
Contributors and their role
Francesca Re wrote the review article.
Maria Gregori deal with bibliographic research.
Massimo Masserini set up the work and reviewed the manuscript.
Competing interests
The authors Francesca Re, Maria Gregori and Massimo Masserini declare that they have no significant competing financial, professional or personal interests that might have influenced the performance or presentation of the work described in this manuscript.
Provenance and peer review
Commissioned, externally peer reviewed.
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