阅读说明：本技术 用于治疗神经元障碍的纳米粒子 (Nanoparticles for the treatment of neuronal disorders ) 是由 马里-艾迪斯·梅尔 劳伦特·莱维 艾格内斯·波迪尔 于 2018-12-18 设计创作，主要内容包括：本发明涉及医学领域,特别是涉及神经系统障碍的治疗。更具体而言,本发明涉及一种纳米粒子或纳米粒子聚集体,其用于预防或治疗对象的神经系统疾病或其至少一种症状而无需将所述纳米粒子或纳米粒子聚集体暴露于电场,并优选无需将其暴露于任何其他外部激活源,其中所述纳米粒子或纳米粒子聚集体的材料选自导体材料、半导体材料、介电常数ε<Sub>ijk</Sub>等于或高于200的绝缘体材料、和介电常数ε<Sub>ijk</Sub>等于或低于100的绝缘体材料。本发明还涉及包含这样的纳米粒子和/或纳米粒子聚集体的组合物和试剂盒,及其在无需将其暴露于电场并优选无需将其暴露于任何其他外部激活源的情况下的用途。(The present invention relates to the field of medicine, and in particular to the treatment of neurological disorders. More particularly, the present invention relates to a nanoparticle or nanoparticle aggregate for use in the prevention or treatment of a neurological disease or at least one condition thereof in a subjectWithout exposing the nanoparticles or nanoparticle aggregates to an electric field, and preferably without exposing them to any other external activation source, wherein the material of the nanoparticles or nanoparticle aggregates is selected from the group consisting of a conductive material, a semiconducting material, a dielectric constant ijk Insulator material of 200 or more, and dielectric constant ijk Insulator material equal to or lower than 100. The invention also relates to compositions and kits comprising such nanoparticles and/or nanoparticle aggregates and their use without exposing them to an electric field and preferably without exposing them to any other external activation source.)

1. A nanoparticle or aggregate of nanoparticles for use in the prevention or treatment of a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticle or aggregate of nanoparticles to an electric field or any other external activation source, wherein the material of the nanoparticle or aggregate of nanoparticles is selected from the group consisting of a conductive material, a semi-conductive material, a dielectric constant material_ijkInsulator material of 200 or more, and dielectric constant_ijkAn insulator material equal to or lower than 100, wherein i) when said material is a conductor material, a semiconductor material or a dielectric constant_ijkEqual to or higher than 200 of insulator material, the median largest dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm, and wherein ii) the cores of the nanoparticles or nanoparticle aggregates are coated with a biocompatible coating layer providing a neutral or negative surface charge when measured in an aqueous solution with an electrolyte concentration between 0.001 and 0.2M, a nanoparticle or nanoparticle aggregate material concentration between 0.01 and 10g/L and a pH between 6 and 8.

2. Nanoparticle or nanoparticle aggregate for use according to claim 1, wherein the material of the nanoparticle or nanoparticle aggregate is a conductor material selected from metals having a standard reduction potential E ° higher than 0.2 and organic materials having contiguous sp2 hybridized carbon centers in their structure.

3. The nanoparticle or nanoparticle aggregate for use according to claim 2, wherein the material of the nanoparticle or nanoparticle aggregate is selected from metal nanoparticles, wherein the metal element is Ir, Pd, Pt, Au or any mixture thereof, and organic nanoparticles consisting of polyaniline, polypyrrole, polyacetylene, polythiophene, polycarbazole and/or polypyrene.

4. The nanoparticle or nanoparticle aggregate for use according to claim 1, wherein the material of the nanoparticle or nanoparticle aggregate is a semiconductor material with a band gap Eg below 3.0 eV.

5. The nanoparticle or nanoparticle aggregate for use according to claim 4, wherein the material of the nanoparticle or nanoparticle aggregate consists of elements of group IVA of the Mendeleev's periodic Table, or is a mixed composition of elements of groups III and V of the Mendeleev's periodic Table, or is a mixed composition of elements of groups II and VI of the Mendeleev's periodic Table.

6. The nanoparticle or nanoparticle aggregate for use according to claim 5, wherein the material of the nanoparticle or nanoparticle aggregate consists of elements of group IVA of the Mendeleev's periodic Table and is doped with charge carriers selected from Al, B, Ga, In and P.

7. The nanoparticle or nanoparticle aggregate for use according to claim 1, wherein the material is an insulator material with a band gap Eg equal to or higher than 3.0eV and the relative permittivity_ijkBetween 20 ℃ and 30 ℃ and at 10²Hz up to infrared frequencies.

8. The nanoparticle or nanoparticle aggregate for use according to claim 7, wherein said material is an insulator material with a band gap Eg equal to or higher than 3.0eV and said relative permittivity_ijkEqual to or higher than 200, and the material of the nanoparticles or nanoparticle aggregates is a dielectric material selected from BaTiO₃、KTaNbO₃、KTaO₃、SrTiO₃And BaSrTiO₃Mixed metal oxide of。

9. The nanoparticle or nanoparticle aggregate for use according to claim 7, wherein said material is an insulator material with a band gap Eg equal to or higher than 3.0eV and said relative permittivity_ijkEqual to or lower than 100 and the material of the nanoparticles or nanoparticle aggregates is selected from ReO₂、ZrO₂And HfO₂The metal oxide of (1).

10. The nanoparticle for use according to any one of claims 1 to 9, wherein the neurological disease is selected from parkinson's disease, alzheimer's disease, epilepsy, obsessive compulsive disorders, autism spectrum disorders, depression, dystonia, Tourette's syndrome, schizophrenia, stroke, aphasia, dementia, tinnitus, huntington's disease, essential tremor, bipolar disorder, anxiety, an addictive disorder, a conscious vegetative state and at least one symptom thereof.

11. A composition comprising the nanoparticles and/or nanoparticle aggregates of any one of claims 1 to 9 and a pharmaceutically acceptable carrier, wherein the composition is for use in preventing or treating a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticles and/or nanoparticle aggregates to an electric field or any other external activation source.

12. The composition for use according to claim 11, wherein the composition comprises at least two different nanoparticles and/or nanoparticle aggregates of any one of claims 1 to 9.

13. A kit comprising at least two different nanoparticles and/or nanoparticle aggregates of any one of claims 1 to 9.

14. The kit of claim 13, for use in preventing or treating a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticles and/or nanoparticle aggregates to an electric field or any other external activation source.

Background

Neurological disorders are a significant health problem (Neurological disorders public health challenges, WHO, 2006). Impairment of neural network function can have different origins. Parkinson's disease is a movement disorder caused by the death of dopamine neurons located in the substantia nigra of the midbrain. Stroke corresponds to a blockage of the blood supply to the brain. In the absence of oxygen, neurons in the affected area die, and the body parts controlled by those cells also fail to function. Huntington's disease is a genetic disorder. Epilepsy is a disorder caused by abnormal excitation of a large number of neurons in various brain regions. Alzheimer's disease is a neurodegenerative disorder characterized by neuronal death in the hippocampus, cerebral cortex and other brain regions. The cause of autism spectrum disorders is multifactorial: genetic, environmental, etc.

Neurological disorders can be classified according to the chief symptoms affecting the patient. Three main types of symptoms are observed: movement disorders, mental (emotional/social) disorders and cognitive disorders, as further explained below.

Dyskinesias include tremor, hypokinesias such as bradykinesia or dyskinesia, muscular contortions, stiffness, postural instability, freezing gait, and the like. Diseases that exhibit dyskinesias typically include parkinson's disease, dystonia, epilepsy, huntington's disease, and Tourette's syndrome.

Mental disorders constitute various diseases that exhibit symptoms of emotional/social disorders. A non-exhaustive list includes autism spectrum Disorders, schizophrenia, bipolar Disorders, depression, anxiety Disorders, obsessive-compulsive Disorders, substance-related and/or addictive Disorders (defined from the Diagnostic and Statistical handbook of mental Disorders, 2013, fifth edition, the American psychiatric Association). Some patients with movement disorders such as parkinson's disease and dystonia may develop mental disorders later in the disease.

Cognitive disorders are present in many, if not all, mental disorders (e.g., schizophrenia, bipolar disorder). Only disorders whose core feature is cognition are included in the cognitive disorder category. Cognitive disorders affect the daily life of a patient: simple tasks become complicated to implement. Dementia is a representative cognitive disorder, a generic term for a decline in mental ability that is severe enough to interfere with daily life. Alzheimer's disease is a particular type of dementia, with one side being neurodegenerative.

Where possible, neurological disorders are treated with drugs that modulate neurotransmitter levels in the brain and control their interaction with their specific neurotransmitter receptors. The main neurotransmitters involved are: glutamic acid, gamma-aminobutyric acid (GABA), dopamine, and acetylcholine. Glutamate and GABA neurotransmitters are of particular interest as they play a major Role in increasing (Platt et al, The Veterimental Journal, 2007, 173, 278:286: glutamate in central nervous system health and disease-review (The Role of glutamate in central nervous system health and disease-a review)) and decreasing neuronal excitability, respectively (Holmes et al, mental recording and development disorders, 1995, 1, 208:219: glutamate and GABA roles in epileptic pathophysiology (Role of glutamate and GABA in The pathophysiology of epilepsy). Dopamine is involved in several brain functions: control of movement via the basal ganglia (inappropriate dopamine levels in the basal ganglia lead to uncontrolled movement), pleasure reward seeking behavior (disorder may lead to addiction to dysfunction), cognition (dopamine disturbance in the frontal lobe may lead to decline in neurocognitive function), etc. (Alcaro et al, Brain res. rev., 2007, 56(2), 283- > 321: the Behavioral function of the mesolimbic dopaminergic system: the neuro-Behavioral view of affective nerves). Acetylcholine is a neurotransmitter involved in learning and memory at The level of The central nervous system (Hasselmo et al, Curr Opin Neurobiol, 2006, 16(6), 710-.

A common drug that reduces motor symptoms of parkinson's disease is levodopa, which converts to dopamine in the brain and in this way helps balance dopamine deficiency. Levodopa is combined with carbidopa, which helps to avoid the conversion of levodopa to dopamine throughout the body. One problem with levodopa treatment is The "on-off" phenomenon, which results in alternating periods of immobility and incapacitation associated with depression with periods of relaxation of cheerfulness (Lees et al, J Neurology neurosergy psychiatry, supplement in particular, 1989, 29-37: on-off phenomenon). The unresponsiveness of advanced Parkinson's disease patients to this treatment is a problem (Fabbri et al, Parkinson's disease and related disorders, 2016: does advanced Parkinson's disease patients still respond to levodopa. Other common drugs that treat symptoms of neuropsychiatric disorders such as "positive" symptoms, delusions, and hallucinations in schizophrenia are antipsychotics.

However, the symptoms of the therapeutic treatment of neurological disorders with these drugs are non-specific and, therefore, they may cause serious adverse events. In addition, refractoriness to used drugs may occur.

As understanding of neuroscience advances, the brain can be thought of as an electrical network through which wires, neurons, encode and transmit information. Connectivity between neurons is simple and complex: simply because it consists in the influx/efflux of ions inside the neuron, generating action potentials (or "spikes" of electrical activity); the complexity is due to The fact that brain networks are composed of hundreds of millions of neurons that form nodes, hubs, and modules that exhibit coordinated interactions at various spatial and temporal scales (fortito et al, Nature Reviews Neuroscience, 2015, 16, 159-172: connectivity of brain disorders). Neural communication depends on anatomical components (structures) connecting individual neurons and processes (functions) of transferring information. Both of these aspects affect the overall performance of the nervous system. Oscillations of brain electrical activity patterns, which are typically measurable by electroencephalography (EEG), are detrimental to neuronal interactions. Different oscillation frequency bands are observed: θ, α, β, γ (Ward et al Trends in Cognitive Sciences, 2003, 7(12), 553: (Synchronous neural oscillations and Cognitive processes)). Structurally, the most striking neuroanatomical feature of the brain is the rich connectivity between neurons, which reflects the importance of neural communication. Synchronization of oscillations between one brain region and another ("synchronization") seems to constitute the last stage of information encoding [ first stage (neurons) by introducing space-time coordination: an action potential; second stage (neuronal network): neuronal oscillations ] (Engel et al, Nature Reviews Neuroscience, 2001, 2, 704: 716: Dynamic prediction: oscillations and synchronization in top-down processing (Dynamic predictions: oscillations and synchronization in top-down processing)). Importantly, emerging evidence suggests that a subtle balance of spatial and temporal synchronization and desynchronization patterns is fundamental to the functional performance of the nervous system (Schnitzler et al, Nature reviews neuroscience, 2005, 6, 285; 296: Normal and pathological oscillatory communication in the brain).

Dyssynchrony (either too high and/or too long synchrony, also known as supersynchrony, or too low synchrony, also known as impaired synchrony) is associated with several brain disorders such as epilepsy, schizophrenia, dementia and Parkinson's disease (Schnitzler et al, Nature Reviews Neuroscience, 2005, 6, 285-.

Today, modulation of the electrical activity pattern of neurons (neuromodulation) can be induced by electrical stimulation. Current techniques for generating electrical stimulation into the brain induce an electric field using direct electrical stimulation or by applying a current through a magnetic coil. Because certain neurological disorders affect areas in the deep brain and because of the weak depth of penetration of the electric field, surgically implanted electrodes within the brain have been implemented to continuously deliver electrical stimulation and constitute a "deep brain stimulation" (DBS) technology. The efficacy depends on the parameters used for stimulation, in particular the frequency. In 1987, high frequency stimulation (. gtoreq.100 Hz) of the abdominal intermediate nucleus (VIM) with implanted electrodes was found to alleviate the tremor symptoms in patients with Parkinson's disease (Benabid et al, Applied neurology, 1987, 50, 344-346: Combined (thalamotomy and stimulation) stereotactic surgery on the thalamic nucleus of VIM for bilateral Parkinson's disease (combined (thalamotomy and stimulation) stereotactic surgery). Also, it has been shown in monkeys that high frequency Stimulation (>100Hz) allows for changes in the temporal firing pattern of neurons in the lateral (GPe) and medial (GPi) globus (stimulus-synchronized regular firing pattern) compared to low frequency Stimulation (<50Hz), which blocks the transmission of altered neuronal activity patterns in the basal ganglia to its target structures in the thalamus and brainstem, thereby alleviating the symptoms of bradykinesia and stiffness (Hashimoto et al, the journal of Neuroscience, 2003, 23(5), 1916:1923: Stimulation of the subthalamic nucleus alters the firing pattern of pallidal neurons)). DBS is now approved for the treatment of several movement disorders (parkinson's disease, dystonia, essential tremor, epilepsy) and psychiatric disorders (obsessive compulsive disorder, depression).

However, several disadvantages may be associated with DBS, above all the invasiveness of the technique and the risk of various complications such as bleeding, seizures, infection, guidewire migration, guidewire breakage, etc. (Fenoy et al, J Neurosurg, 2014, 120, 132-.

The Focality (i.e., spatial resolution) of the generated electric field in the target is another problem. The spread of electrical stimulation is also associated with side effects such as depression. Much research has been devoted to designing new electrode types that can transport and limit stimulation in certain areas (Luan et al, front in Neuroengineering, 2014, 7(27), 1-9: Neuromodulation: present and emerging methods). Other technical aspects are evaluating: electrodes (or leads), their size, the invasiveness of the DBS device, the materials from which the leads are constructed, compatibility with (magnetic resonance) imaging techniques, Internal Pulse Generator (IPG) battery life associated with sustained stimulation requirements.

The main other existing types of electrical stimulation, namely transcranial electrical stimulation or transcranial magnetic stimulation, have the advantage of being non-invasive, but the penetration depth of the electric field is weak. Their application is therefore limited to stimulation of the cerebral cortex (failure to reach the deep brain). Moreover, the spatial resolution is still poor.

The present invention relates to nanoparticles and/or nanoparticle aggregates (aggregates of nanoparticles) for use in the prevention or treatment of a neurological disease, typically a neuronal network disorder, or at least one symptom thereof.

The nanoparticles or nanoparticle aggregates normalize the synchronization of neuronal oscillations within and/or between neuronal networks, and within and/or between different regions of the brain (improve synchronization). The nanoparticles or nanoparticle aggregates described herein by the inventors thereby help the subject/patient to return to a healthy/normal state.

The nanoparticles and nanoparticle aggregates described herein by the inventors do not require the application/induction of an electrical current or an electrical field/stimulus, and preferably do not require exposure to any other external activation source such as a light source, a magnetic field, or an ultrasound source in order to function (i.e., be effective). The nanoparticles and nanoparticle aggregates described herein do not require exposure to an electric current or electric field/stimulus, and preferably do not require exposure to any other external activation source such as a light source, magnetic field or ultrasound source to be able to function in the context of the uses described herein. The inventors have found that these nanoparticles or nanoparticle aggregates can advantageously and surprisingly be effectively used without exposing them or the subject to which they are administered to an electric current or electric field/stimulation, typically an electric current or electric field/stimulation applied to said subject, e.g. by Deep Brain Stimulation (DBS), Transcranial Electrical Stimulation (TES) or Transcranial Magnetic Stimulation (TMS), and preferably without exposing them to any other external activation source, such as a light source, a magnetic field or an ultrasound source. This means that, thanks to the present invention, the treated subject will not suffer from the negative side effects of exposure to electric currents or electric fields/stimuli or any other external activation source, such as a light source, a magnetic field or an ultrasound source.

As is well known to those skilled in the art, nanoparticles have an enhanced/high surface area to volume ratio, typically about 35-40% of the atoms of a 10nm nanoparticle are located on the surface, compared to less than 20% of nanoparticles having a size above 30 nm. This high surface area to volume ratio is associated with the strong surface reactivity which is size dependent. Thus, nanoparticles (especially nanoparticles smaller than 20 nm) may exhibit novel properties compared to bulk materials. For example, gold particles are known to be chemically inert and resistant to oxidation on a macroscopic scale, while gold particles below 10nm in size have a chemically active surface. The toxicity mechanisms associated with Chemical destabilization of metal nanoparticles may be (i) the direct release of the metal in solution (dissolution process), (ii) the catalytic properties of the metal nanoparticles, and (iii) the redox evolution of the nanoparticle surface, which can oxidize proteins, generate Reactive Oxygen Species (ROS), and induce oxidative stress (see m.affan et al, Environmental Pollution 157(2009) 1127-1133: Chemical Stability of the metal nanoparticles: parameters for controlling their potential cytotoxicity in vitro (Chemical Stability of metallic nanoparticles: a parameter controlling the potential cytotoxicity of cellular toxicity in vitro)).

Cerium oxide (7nm — CeO) in addition to the gold nanoparticles exhibiting catalytic properties described above₂Particles) or iron oxide (20 nm-Fe)₃O₄Particle) nanoparticles also show redox modification of their surface, leading to cytotoxic effects associated with oxidative stress in vitro (see m.affan et al, Environmental Pollution 157(2009) 1127-1133: chemical stability of metal nanoparticles: parameters for controlling the potential cytotoxicity in vitro (Chemical Stability of metallic nanoparticles: a parameter controlling the cytotoxic activity in vitro)). Likewise, 11 nm-silicA nanostructures are also attacked by biological mediA (see S-A Yang et al, Scientific Reports 20188: 185: reiteration on the stability of silicA nanoparticles in biological mediA).

Thus, as the inventors hereinafter explain, when intended for in vivo use in a subject, typically a mammal, in particular a human, nanoparticles having a size below 30nm are carefully selected.

Disclosure of Invention

Nanoparticles or nanoparticle aggregates are advantageously described herein for the first time,for use in preventing or treating a neurological disease or at least one symptom thereof in a subject in need thereof without exposing the nanoparticles or nanoparticle aggregates to an electric field, and preferably without exposing them to any other external activation source, such as a light source, a magnetic field or an ultrasound source. The material of the nanoparticle or nanoparticle aggregate is typically selected from the group consisting of a conductive material, a semiconductive material, a dielectric constant_ijkInsulator material of 200 or more, and dielectric constant_ijkInsulator material equal to or lower than 100.

In one particular aspect, the inventors describe herein a nanoparticle or aggregate of nanoparticles for use in preventing or treating a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticle or aggregate of nanoparticles to an electric field or any other external activation source, wherein the material of the nanoparticle or aggregate of nanoparticles is selected from the group consisting of a conductive material, a semiconductive material, a dielectric constant material_ijkInsulator material of 200 or more, and dielectric constant_ijkAn insulator material equal to or lower than 100, wherein i) when said material is a conductor material, a semiconductor material or a dielectric constant_ijkEqual to or higher than 200 of insulator material, the median largest dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm, and wherein ii) the cores of the nanoparticles or nanoparticle aggregates are coated with a biocompatible coating layer providing a neutral or negative surface charge when measured in an aqueous solution with an electrolyte concentration between 0.001 and 0.2M, a nanoparticle or nanoparticle aggregate material concentration between 0.01 and 10g/L and a pH between 6 and 8.

Also described herein is the use of a nanoparticle or nanoparticle aggregate for the preparation of a composition for preventing or treating a neurological disease as described herein or at least one symptom thereof in a subject in need thereof without exposing the nanoparticle or nanoparticle aggregate to an electric field, and preferably without exposing it to any other external activation source, such as a light source, a magnetic field or an ultrasound source.

Also described herein are methods for preventing or treatingA composition of a neurological disease or at least one symptom thereof in a subject, wherein the composition comprises or consists of a nanoparticle and/or aggregate of nanoparticles and a pharmaceutically acceptable carrier, wherein the material of the nanoparticle or aggregate of nanoparticles is typically selected from the group consisting of a conductor material, a semiconductor material, a dielectric constant material, and a pharmaceutically acceptable carrier_ijkInsulator material of 200 or more, and dielectric constant_ijkAn insulator material equal to or lower than 100, and wherein said preventing or treating is performed without exposing the nanoparticles or nanoparticle aggregates applied to said subject by said composition to an electric field and preferably without exposing it to any other external activation source such as a light source, a magnetic field or an ultrasound source.

Also described herein are kits comprising or consisting of at least two different nanoparticles and/or nanoparticle aggregates, each nanoparticle or nanoparticle aggregate consisting of a material generally selected from the group consisting of a conductive material, a semiconductive material, a dielectric constant_ijkInsulator material of 200 or more, and dielectric constant_ijkA different material composition of the insulator material equal to or lower than 100, and the use of said kit in/in a method of preventing or treating a neurological disease or at least one symptom thereof in a subject, generally without exposing said nanoparticles or nanoparticle aggregates to an electric field and preferably without exposing them to any other external activation source, such as a light source, a magnetic field or an ultrasound source.

Detailed Description

The Human nervous system is estimated to consist of approximately 800-. A defining characteristic of a neuron (or nerve cell) is its ability to transmit electrical signals in the form of action potentials.

Neurons/nerve cells constitute the fundamental nodes of the brain. Neural cells can communicate with each other in a highly structured manner, forming a network of neurons. Neurons communicate via synaptic connections. Within neurons, the nanocircuit constitutes the basic biochemical mechanism for mediating the occurrence of key neuronal properties such as learning and memory, and neuronal rhythmicity.

Only a few interconnected neurons can form a microcircuit and can perform complex tasks such as mediating reflexes, processing sensory information, initiating motor, and learning and memory mediation. A macro-loop is a more complex network composed of multiple embedded micro-loops. The macrocircuit mediates higher brain functions such as object recognition and cognition. Thus, the multi-stage network occupies the nervous system.

Excitability of neural network

Neurons send messages electrochemically (i.e., chemicals/ions cause electrical signals). Important ions in the nervous system are sodium and potassium, calcium and chloride. When a neuron does not send a signal, it is "quiescent". When a neuron is at rest, the interior of the neuron is negative with respect to the exterior. Although the concentrations of different ions attempt to equilibrate on both sides of the membrane, they cannot because the cell membrane allows only some ions to pass through the channel (ion channel). In addition to these selective ion channels, there are pumps that use energy to move three sodium ions out of the neuron for every two potassium ions that are put in. Finally, when all these forces are balanced and the voltage difference between the interior and exterior of the neuron is measured, the resting membrane potential (also called "resting potential") of the neuron is about-70 mV. This means that the interior of the neuron is 70mV lower than the exterior. At rest, there are relatively many sodium ions outside the neuron and relatively many potassium ions inside the neuron. Action potentials (also identified as "spikes" or "pulses") occur when neurons send information along axons away from the cell body. This means that certain events (stimuli) cause the resting potential to move towards 0 mV. When depolarization reaches approximately-55 mV, the neuron fires an action potential. If the depolarization does not reach the critical threshold level, no action potential is emitted (on/off mechanism). In addition, when a threshold level is reached, an action potential of fixed amplitude is always delivered. Thus, either depolarization does not reach the threshold or a full action potential is generated.

A large variability in the propagation velocity of the action potential was found. In practice, the propagation velocity of action potentials in nerves can vary from 100 m/s to less than one tenth of a m/s. However, the time constant is an indicator of how quickly the membrane responds to the stimulus in time, and the spatial constant (also the length constant) is an indicator of how well the potential spreads along the axon, as a function of distance.

Connectivity within and between neural networks

There are three types of connectivity networks used to study intra-brain and cross-brain communications. Structural connectivity is based on the detection of fiber tracks that physically connect brain regions. These are anatomical network maps that indicate the possible ways in which signals may travel in the brain. Functional connectivity identifies activity in brain regions with related activity of similar frequency, phase, and/or amplitude. Effective connectivity uses functional connectivity information and further determines the direct or indirect impact one nervous system may have on another, more specifically the direction of dynamic information flow in the brain (Bowyer et al, Neuropsychiatric Electrical, 2016, 2(1), 1-12: Coherence-a measure of the brain network: past and present (Coherence a measure of the brain networks: past and present)).

Synchronous activity within a neuronal network can be detected by Magnetoencephalography (MEG), electroencephalography (EEG), Functional Magnetic Resonance Imaging (FMRI), or Positron Emission Tomography (PET), and then imaged using network connectivity analysis. MEG (magnetoencephalogram) or EEG (electroencephalogram) are preferred because they have high temporal resolution to resolve dynamic information flow. Connectivity analysis of the brain is performed to map out the communication networks required for the brain to function. Specific areas in the brain are dedicated to processing certain types of information. Imaging techniques have revealed that these areas connect and communicate with other specialized areas throughout the network in the brain. "Coherence" (Bowyer et al, Neuropsychiatric Electrical, 2016, 2(1), 1-12: Coherence-a measure of brain network: past and present (Coherence a measure of the brain network: past and present)) is a mathematical technique that quantifies the frequency and amplitude of synchronicity (in a synchronized or in-synchronization state) of neuronal patterns of oscillatory brain activity. Detecting the synchronous activation of neurons can be used to determine the health or integrity of functional connectivity in the human brain. Superimposing a functional connectivity map onto a structural connectivity image and exploiting the direction of information flow obtained from the effective connectivity provides a comprehensive understanding of how the brain functions. These techniques help to evaluate treatment methods based on pre-treatment and post-treatment brain connectivity imaging.

The intact (i.e., "normal" or "healthy") brain expresses complex ("normal" or "healthy") patterns of synchronized activity, associated with different 'states' of the organism, ranging from slow rhythms (0.5-4Hz), to θ (4-8Hz), α (8-12Hz), β (15-30Hz), and γ (30-70Hz) oscillations. Interestingly, the scatter culture of cortical structures provides a convenient system for examining the regulatory rules for the occurrence, generation and propagation of network firing (spikes) and outbreaks (spike clusters) in densely interconnected neuronal populations. Network activity can be recorded for long periods of time in a non-invasive manner and with limited time resolution using a multi-electrode array. The two-dimensional scatter culture can be used as a viable test system for studying regulatory rules for the formation and maintenance of network activity in the Brain, allowing testing of unresolved hypotheses in the intact Brain (Cohen E. et al Brain Research, 2008, 1235, 21-30: Determinants of spontaneous activity in the cultured hippocampal network (deterinal of specific activity in networks of small hippopathic animals)).

Advantageously described herein for the first time are nanoparticles or nanoparticle aggregates for use in preventing or treating a neurological disease or at least one symptom thereof in a subject in need thereof without exposing said nanoparticles or nanoparticle aggregates to an electric field, and preferably without exposing them to any other external activation source, such as a light source, a magnetic field or an ultrasound source. Such exposure to a (therapeutic or diagnostic) electric field or any other (therapeutic or diagnostic) external activation source, such as a light source, a magnetic field or an ultrasound source, is generally understood herein as a therapeutic or diagnostic exposure, typically performed by medical personnel, e.g. by a doctor or nurse.

The material of the nanoparticle or nanoparticle aggregate is typically selected from the group consisting of a conductive material, a semiconductive material, a dielectric constant_ijkInsulator material of 200 or more, and dielectric constant_ijkInsulator material equal to or lower than 100.

The term "treatment" refers to a therapeutic treatment or measure capable of preventing, alleviating or curing a disease, disorder or dysfunctional condition as described herein. Such treatment is intended for use in a mammalian subject, preferably a human subject in need thereof. Contemplated for this is a subject that has been identified (diagnosed) as having a disease, disorder, or dysfunctional state as described herein, or is considered "at risk" for such a disease, disorder, or dysfunctional state for which the treatment is prophylactic or preventative treatment.

In a particular aspect, the subject is not a subject with epilepsy.

Abnormal modulation of oscillatory communication between neurons does exist in different types of neurological diseases or disorders (also referred to herein as "neurological diseases or disorders") (Uhlhaas et al, Neuron, 2006, 52, 155.

The human nervous system is divided into the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS is subdivided into the brain and spinal cord, which are located in the cranial cavity and the spinal canal of the skull, respectively. The CNS and PNS work in concert to integrate sensory information and control motor and cognitive functions. Figure 1 shows a simplified diagram of the brain structure.

Synchronization (or synchronization) within and/or between networks of neurons, within and/or between different regions of the brain, is performed by coordinating Neuronal oscillations in time (Buzsaki et al, Science, 2004, 304, 1926: (neural oscillations in cortical networks)).

Dyskinesias in subjects are often due to hyper-synchrony, which means that the synchronization of oscillations within and/or between neuronal networks within and/or between different regions of the brain, which is usually observed on electroencephalography (EEG), is too high and/or too long ("excessive") compared to healthy/normal subjects.

Mental and cognitive disorders in subjects are usually due to impaired synchrony, which means that the synchrony of oscillations within and/or between neuronal networks in and/or between different regions of the brain, which is usually observed on EEG, is reduced (usually shows reduced activity) or even disappears, i.e. is not detectable, compared to healthy/normal subjects (see table 1: abnormal neurosynchrony in neurological disorders (adapted from uhlaas et al, Neuron, 2006, 52, 155:168: neurosynchrony in brain disorders: correlation of cognitive dysfunction and pathophysiology).

TABLE 1：

Since "Coherence" is a mathematical technique that quantifies the frequency and amplitude of synchronicity (in a synchronized or synchronizing state) of neuronal patterns of oscillatory brain activity in a subject, it can be considered that too high and too low Coherence compared to healthy/normal subjects relates to dyskinesia and psycho/cognitive disorders, respectively (Bowyer et al, Neuropsychiatric Electrophysiology, 2016, 2(1), 1-12: Coherence-a measure of the brain network: past and present (Coherence of the brain networks): past and present) (see fig. 2).

In a particular aspect, the neurological disease or disorder targeted in the context of the present invention is selected from parkinson's disease, alzheimer's disease, epilepsy, obsessive-compulsive disorders, autistic spectrum disorders, depression, dystonia, Tourette's syndrome, schizophrenia, stroke, aphasia, dementia, tinnitus, huntington's disease, essential tremor, bipolar disorders, anxiety, addiction, conscious vegetative state, for example selected from parkinson's disease, alzheimer's disease, epilepsy, obsessive-compulsive disorders, autistic spectrum disorders, depression, dystonia, Tourette's syndrome, schizophrenia, stroke, aphasia, dementia, tinnitus, huntington's disease, essential tremor, bipolar disorders, addiction, conscious vegetative state and at least one symptom thereof.

As already explained above, neurological diseases or disorders may be classified according to the chief symptoms affecting the patient, which are movement disorders, mental (emotional/social) disorders and cognitive disorders, as further detailed below.

Examples of movement disorders

Parkinson's disease

Parkinson's Disease (PD) affects approximately 700 to 1000 million people worldwide and is characterized by tremor, abnormal movement, bradykinesia, freezing gait, and the like. PD is a slowly progressing degenerative disease of the brain. It affects nerve cells in the brain in areas known as the basal ganglia and the substantia nigra. The nerve cells in the substantia nigra produce dopamine, a neurotransmitter that acts as a chemical messenger in the brain circuit and is important for planning and controlling body movements. In PD, dopamine-producing substantia nigra nerve cells die prematurely in some individuals (Corti et al, Physiol Rev, 2011, 91, 1161. 1218: What is known about the etiology and mechanistic genetics of Parkinson's disease (What genetics tells about the cause and mechanistic of Parkinson's disease)). When dopamine receptors in the striatum are not properly stimulated, some of the basal ganglia are under-or over-stimulated. In particular, the subthalamic nucleus (STN) becomes hyperactive and acts as an accelerator of the medial pallidum (GPi). Over-stimulation of GPi has an over-inhibitory effect on the thalamus, which in turn reduces thalamic output and leads to motor slowing and stiffness (Guo et al, front in computerized Neuroscience, 2013, 7, 124, 1-11: Basal ganglia modulation of thalamocortical relay in Parkinson's disease and dystonia (Basal ganglia modulation of cerebral cortical relay in parkinsons' and dystonia)).

The lack of dopamine in PD is associated with excessive oscillatory synchronization of the beta frequency throughout the cortical-basal ganglia motor network. Indeed, dopamine levels in the basal ganglia are expected to inhibit beta-synchrony, which in turn mediates the dopaminergic involvement necessary for motor prediction (Jenkinson et al, Trends in Neuroscience, 2011, 34(12), 611-. If dopamine levels in the basal ganglia are not high enough, the beta oscillations are no longer controlled to be synchronized and bradykinesia may occur. Another observation in parkinson's disease patients leads to the conclusion that: cortical oscillations in The beta band cause and drive cortical oscillations in The basal ganglia (Lalo et al, The Journal of Neuroscience, 2008, 28(12), 3008-.

Deep Brain Stimulation (DBS) can be used to treat symptoms of tremor and stiffness (Eusebio et al, J neurosurg Psychiatry, 2011, 82, 569. sup. sup. 573: Deep brain stimulation can inhibit pathological synchronization in Parkinson's disease patients (Deep brain stimulation of Parkinson's disease). Treatment of PD symptoms by DBS has gained FDA approval since 2002 (essential tremor since 1997). Electrical stimulation is typically performed in the basal ganglia, STN and GPi. As mentioned above, cortical beta oscillations are also involved in the pathophysiology of the disease, and therefore Transcranial stimulation of the cortex (e.g., Transcranial magnetic stimulation-TMS) may also be used to treat symptoms of Parkinson's disease (Cantello et al Brain Research Reviews, 2002, 38, 309-.

Dystonia

Dystonia is a neurological disorder characterized by abnormal, involuntary tortuosity and steering movements, reflecting impaired motor system function. There are several forms of dystonia depending on the body site affected by the symptoms, the genetic origin, the type of neurotransmitter involved, etc. The Central Nervous System (CNS) of dystonia exhibits inadequate inhibition, which causes a loss of reciprocal spinal cord inhibition between the opposite muscles. For example, in the case of upper limb dystonia, Abnormal synchronization of neurons/nerves that provide input signals to the forearm antagonist muscles leads to co-contraction of these antagonist muscles (dystonia symptoms) (Farmer et al Brain 1998, 121, 801: 814 Abnormal motor unit synchronization of antagonist muscles is the root of pathological co-contraction of upper limb dystonia).

The DBS target that showed interesting anti-dystonia effects was the medial pallidoluysia (GPi-DBS). GPi-DBS was approved by the FDA in 2003 for chronic, medically refractory dystonia patients (Hu et al, Translational neuro-degeneration, 2014, 3(2), 1-5: deep brain stimulation for dystonia (Deepbriin stimulation for dystonia)). Stimulation of the ventral medial (VIM) nucleus of the thalamus (VIM-DBS) produces much less robust effects. Experiments have been performed using hypothalamic nucleus stimulation (STN-DBS). GPi-DBS provides relief from the major symptoms of dystonia, but may take weeks to months to fully produce a therapeutic effect (Dressler et al, JNeural Transm, 2015, DOI10.1007/s 00702-015-1453-x: Strategies for treating dystonia (Strategies for treatment of dystonia)).

Epilepsy

Epilepsy is a brain disorder affecting approximately 5000 million people worldwide and is characterized primarily by repeated and unpredictable interruptions in normal brain function, known as seizures. Epilepsy is not a single disease entity, but reflects a variety of disorders of deep brain dysfunction that can be caused by many different causes (gene mutations, brain tumors, head trauma, stroke, alcoholism, brain inflammation, infections such as meningitis, HIV or viral encephalitis, etc.) (Fisher et al, Neurology, 2015, 28(2), 130-: Redefining epilepsy (Redefining epilepsy)).

Seizures are defined as the transient manifestations and/or symptoms due to excessive synchronous neuronal activity in the brain (Fisher et al, Epilesia, 2005, 46(4), 470-; seizures and Epilepsy: the definitions proposed by the International anti-Epileptic Association (ILAE) and the International Bureau of Epilepsy (IBE) (Epileotic conditions and Epilepsy: definitionssproposed by the International League Aging Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE))). The cerebral cortex is the main unit for producing seizures: many people are diagnosed with focal frontal or medial temporal attacks (national institute of Neurological Disorders and Stroke): http:// www.ninds.nih.gov/Disorders/epilepsy/detail _ epilepsy. htm #3109_ 7). Identification of regions of elevated or "oversynchronous" local synchrony in the cortex suggests that local oversynchrony may be a hallmark of the region of seizure onset (Schevon et al, neuroiamage, 2007, 35(1), 140- "148: epileptic Cortical abnormalities revealed by local EEG synchrony (cardiac antigenic Cortical hormone).

The neural stimulation used to treat epilepsy may take the form of peripheral neural stimulation, such as Vagus Nerve Stimulation (VNS); spinal cord stimulation; transcranial brain stimulation (TES or TMS); or Deep Brain Stimulation (DBS). Responsive neural stimulation is another strategy, in which stimulation is delivered only when the onset of an episode is detected. Both VNS and responsive neural stimulation have been FDA approved for the treatment of certain types of epilepsy in the united states. DBS of the thalamic nucleus (ANT) has been approved in the European Union (Fisher et al, Naturereviews Neurology, 2014, 10, 261) 270: Electrical brain stimulation for epilepsy (Electrical stimulation for epilepasy).

Examples of mental disorders (mood/social disorders)

Obsessive Compulsive Disorder (OCD)

Obsessive Compulsive Disorder (OCD) is a common mental disorder that is often chronic, severe and extremely debilitating. It is also often difficult to treat, with a significant proportion of patients not responding or achieving only partial remission.

Functional neuroimaging studies have demonstrated malfunctions in the prefrontal cortex of the eye socket, the basal ganglia and the striatum.

One study indicated that acute OCD symptoms may be associated with abnormally high oscillatory activity in the subthalamic nucleus (STN), particularly in the left hemisphere and in the-alpha (1-12Hz) frequency range (Bastin et al, Cortex, 2014, 60, 145-; 150: Changes in subthalamic nucleus oscillatory activity during obsessive-compulsive symptoms: 2 case reports (Changes of clinical activity in the subthalamic nucleus during the obsessive-compulsive symptoms: twocase reports)). Furthermore, some subthalamic neurons specifically increase their firing rate when questions arise during validation work (Burbaud et al, broad, 2013, 136(1), 304-.

DBS of the inner capsule (VC) and ventral forelimb adjacent to the Ventral Striatum (VS) are approved in the european union for the treatment of severe and highly therapy resistant OCD (VC/VS-DBS).

Autistic spectrum disorders

Autism is a neurodevelopmental syndrome defined by a defect in social interaction and communication and by abnormal restrictive, repetitive behaviors. Autism is a disorder that usually begins in infancy, beginning at the latest in the first three years of life. Autism is a heterogeneous disorder (no two children or adults with Autism have similar conditions), which leads to the concept of "Autism spectrum disorders," which classifies several grades of disease according to the degree of language deficits or general cognitive delay, and according to the severity of social or behavioral symptoms (Lord et al, Neuron, 2000, 28, 355-; Autism spectrum disorders). At one end of this spectrum, autistic individuals are highly functional, enabling them to live independently and remain in employment. Individuals characterized by hypofunction exhibit more severe symptoms: language difficulties (or even headless language), poor social communication, self-injurious behavior (SIB), development of splenic qi, and potentially life threatening aggression. An important trend in the study of brain structure and function in autism is the network involvement of social affective processing: edge systems, face processing systems, and mirror neuron networks. It has been shown that a defect in the synchronization of the oscillations of the gamma-band is associated with the appearance of symptoms (Sinha et al, Neurosurgery Focus, 2015, 38(6), E3: Deep brain stimulation for the treatment of severe autism: from pathophysiology to surgery (Deep brain stimulation for surgery: from pathophysiology therapy).

Two major categories of symptoms that may need treatment in severe autism are social deficits, including being silent and unresponsive to speech, and potentially life threatening SIBs. Amygdala appears to play an important role in the pathophysiology of these abnormalities. Alterations in excitatory or inhibitory control have been implicated in the pathophysiology of autism. Neuromodulation of amygdala targets by DBS may represent a therapeutic intervention for patients with severe autism. Three treatments for DBS have been reported in the literature. The aim of the treatment is mainly to alleviate movement disorders such as stereotypy (repetitive patterns of action) and disease-related self-injurious behaviour (SIB) (Sinha et al, neurosurgy Focus, 2015, 38(6), E3: Deep brain stimulation treatment of severe autism from pathophysiology to surgery (Deep brain stimulation for surgery: from brain stimulation procedure), Stocco et al, Parkinsonism and related disorders 2014, 20, 1035 1036: Deep brain stimulation treatment of severe secondary stereotypy (Deep brain stimulation for severe secondary stereotypy)). In one of these three cases, DBS in the basolateral nucleus has been reported to cause significant improvement in autism-related symptoms such as social contact, affective modulation, and nocturnal sleep (Sturm et al, Frontiers in human neuroscience, 2013, 6, 341, 1-10).

Schizophrenia

Schizophrenia is a chronic psychosis characterized by the following symptoms: positive symptoms, reflecting abnormal mental activity (hallucinations and delusions); negative symptoms, corresponding to a normally existing deficit in mental function (thought disorder, dysesthesia, poverty of speech). As to the cause of disability in life, schizophrenia is located within the top ten.

Significant ventricular enlargement and increased cerebrospinal fluid on the surface of the brain suggests that the brain has atrophied. This loss of gray matter and a reduced number of synaptic structures on neurons suggests that schizophrenia is a neurodevelopmental disorder, which means that brain abnormalities (as opposed to neurodegenerative disorders) have been present in the first patient.

In schizophrenic patients, it has been shown that The impaired neural circuits observed are due to a failure of The synchronization of The gamma-band (Spencer et al, The Journal of Neuroscience, 2003, 23(19), 7407-7411: dyssynchrony in schizophrenia (Abnormal neural synchronization in schizophrenia); Gallinat et al, Clinical neurosology, 2004, 115, 1863-1874: a decrease in The oscillating gamma-band response in untreated schizophrenic patients indicates impaired frontal lobe network processing (Reduced surgery gamma-based and mediated neural networks).

Electroconvulsive therapy (ECT), shock therapy, has proven to be one of the most successful non-drug treatments for schizophrenia (Payne et al, j. psychopath. act, 2009, 15(5), 346: (section I) of Electroconvulsive therapy 368: opinion on the evolution of ECT and current practice). It involves the continuous application of electrical current to the brain, which causes seizures comparable to epileptic seizures.

Electrical stimulation for symptomatic treatment of schizophrenia may also be performed by DBS. For example, DBS of the nucleus accumbens (NAcc) in depression results in relief of anhedonia, i.e. restoration of enjoyment (Schlarfer et al, Neuropsychopharmacology, 2008, 33, 368 377: alleviating anhedonia of refractory major depression to Deep brain stimulation of reward circuits (Deep brain stimulation to relieved anhedonia in reflex major depression)).

Examples of cognitive disorders

Alzheimer's disease

Alzheimer's Disease (AD) is a neurodegenerative disorder that results in the progressive loss of mental intelligence, behavior, function and learning ability. By 2013, 520 million Americans were estimated to have AD, with approximately 200000 people under 65 years and 500 people over 65 years (Alzheimer's details.2013, 9 (2)), 208-.

Recent evidence suggests that cognitive deficits seen in alzheimer's disease are associated with functional disruption of neurocognitive networks. Analysis of the overall EEG synchronization revealed a general reduction in alpha, beta and gamma band synchronization, with an increase in band synchronization. Loss of synchronization of the beta band has been shown to be associated with cognitive impairment in patients with mild Alzheimer's disease (Schnitzler et al, Nature Reviews Neuroscience, 2005, 6, 285-. Clinical studies are ongoing to evaluate the potential of DBSs for the treatment of Alzheimer's disease.

Nanoparticles

Described herein is a nanoparticle or aggregate of nanoparticles for use in accordance with the invention for use in the prevention or treatment of a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticle or aggregate of nanoparticles to an electric field, and preferably without exposing the nanoparticle or aggregate of nanoparticles to any other external activation source, such as a light source, a magnetic field or an ultrasound source, wherein the material of the nanoparticle or aggregate of nanoparticles is typically selected from the group consisting of a conductive material, a semi-conductive material, a dielectric constant material_ijkInsulator material of 200 or more, and dielectric constant_ijkInsulator material equal to or lower than 100.

Size or dimensions of nanoparticles or nanoparticle aggregates

In the spirit of the present invention, the term "nanoparticle" or "nanoparticle aggregate" refers to a product, in particular a synthetic product, having a size in the nanometer range, typically between 1nm and 1000nm, or between 1nm and 500nm, for example between at least 10nm and about 500nm or about 1000nm, between at least 30nm and about 500nm or about 1000nm, between at least 40nm and about 500nm or about 1000nm, between at least 45nm and about 500nm or about 1000nm, preferably below 500 nm.

The term "aggregate of nanoparticles" or "nanoparticle aggregate" refers to an assembly of nanoparticles that are strongly, usually covalently, bound to each other.

Electron microscopy, such as Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) or cryotem, may be used to measure the size of the nanoparticles or nanoparticle aggregates, more particularly the size of the core of the nanoparticles or nanoparticle aggregates, i.e. the size of the nanoparticles or nanoparticle aggregates without the biocompatible coating. In fact, said biocompatible coating is generally made of compounds (polymeric or organic compounds) mainly composed of light elements, which have a relatively weak elastic interaction with high-energy electrons, resulting in poor image contrast. TEM measures the projected image of particles deposited on an electron transparent substrate. More than 50, preferably more than about 100, 150 or 200 nanoparticles or nanoparticle aggregates recorded per sample should generally be subjected to size assessment measurements. Thus, recording more than about 50, or preferably more than about 100, 150 or 200 nanoparticles or nanoparticle aggregates allows determining the median maximum size of the cores of the nanoparticles or nanoparticle aggregates of the population, and the size of the cores of the nanoparticles or nanoparticle aggregates representing 30% -70% of the percentile of the population of nanoparticles or nanoparticle aggregates. Typical assay protocols can be found in the "NIST-NCL combined assay protocol, PCC-7; measuring dimensions using Transmission Electron Microscopy (TEM); version 1.1 at 12.2009 (NIST-NCL Joint Assay Protocol, PCC-7; Measuring the size of using Transmission Electron Microscopy (TEM); version 1.1December 2009) ".

Likewise, Dynamic Light Scattering (DLS) can also be used to measure the hydrodynamic diameter of a nanoparticle or nanoparticle aggregate in solution (i.e., the diameter of the nanoparticle or nanoparticle aggregate including both its core and its biocompatible coating). The hydrodynamic diameter is the diameter of an equivalent hard sphere that diffuses at the same rate as the analyte. Typical assay protocols can be found in the "NIST-NCL combined assay protocol, PCC-1; measuring the size of nanoparticles in an aqueous medium using batch mode dynamic light scattering; version 1.1 at 2.2010 (NIST-NCL Joint Assay Protocol, PCC-1; Measuring the size of nanoparticles in aqueous media using batch-mode dynamic lighting, version 1.1February 2010). The particle size results obtained from DLS measurements may not be consistent with those obtained from other techniques (e.g., electron microscopy). This is due in part to the difference in the physical properties (e.g., hydrodynamic diffusion and projected area) that are actually measured. Furthermore, DLS is sensitive to the presence of small numbers of large or small particle clusters, whereas electron microscopy generally reflects the size of the primary particles (i.e., the size of the core of the nanoparticle or nanoparticle aggregate) (see NIST-NCL Combined Assay Protocol, PCC-1; measurement of the size of nanoparticles in aqueous media using batch mode dynamic light scattering; version 1.1, 2.2010 (NIST-NCL Joint Assay Protocol, PCC-1; measurement of the size of nanoparticles in aqueous media using a batch mode dynamic light scattering; version 1.1February 2010)).

Both DLS and electron microscopy methods can also be used one after the other to compare dimensional measurements and confirm the dimensions. A preferred method of measuring nanoparticle and nanoparticle aggregate Size is DLS (see International standard ISO22412Particle Size Analysis-Dynamic Light Scattering, International organization for standardization (ISO)2008(International standard ISO22412Particle Size Analysis-Dynamic Light Scattering, International organization for standardization (ISO) 2008)). The average hydrodynamic diameter of the nanoparticles or nanoparticle aggregates measured by DLS in solution is given as a size distribution according to intensity (light scattering intensity is proportional to particle size) and is measured at room temperature (about 25 ℃).

Typically, the largest dimension or size is the diameter of a round or spherical shaped nanoparticle, or the longest length of an oval or elliptical shaped nanoparticle.

The largest dimension of a nanoparticle or aggregate as defined herein is typically between about 2nm and about 250nm or about 500nm, preferably between about 4nm or 10nm and about 100nm or about 200nm, more preferably between about (preferably at least) 10nm and about 150nm, between about (preferably at least) 30nm and about 150nm, between about (preferably at least) 40nm and about 500nm, between about (preferably at least) 45nm and about 500nm, preferably below 500 nm.

DLS techniques are typically used when measuring the average hydrodynamic diameter of a nanoparticle or nanoparticle aggregate in solution. Using DLS, the average hydrodynamic diameter of the nanoparticle or nanoparticle aggregate in solution is typically between about 10nm and about 500nm, preferably between about 10nm or about 30nm and about 100nm or about 500nm, more preferably between about 10nm or about 30nm and about 100nm, about 150nm, about 200nm, about 250nm, about 300nm, about 350nm, about 400nm, about 450nm or about 500 nm.

When measuring the core of a nanoparticle or nanoparticle aggregate, electron microscopy techniques are typically used. Using electron microscopy, the median largest dimension (also referred to herein as the "median largest dimension") of the cores of the nanoparticles or nanoparticle aggregates of the population is typically between about 5nm and about 250nm or about 500nm, preferably about 5nm, about 6nm, about 7nm, about 8nm, about 9nm, about 10nm, about 11nm, about 12nm, about 13nm, about 14nm, about 15nm, about 16nm, about 17nm, about 18nm, about 19nm, about 20nm, about 21nm, about 22nm, about 23nm, about 24nm, about 25nm, about 26nm, about 27nm, about 28nm, about 29nm, about 30nm, about 31nm, about 32nm, about 33nm, about 34nm, about 35nm, about 36nm, about 37nm, about 38nm, about 39nm, about 40nm, about 41nm, about 42nm, about 43nm, about 44nm or about 45nm, about 75nm, about 76nm, about 78nm, about 79nm, about 27nm, about 28nm, about 29nm, about, About 81nm, about 82nm, about 83nm, about 84nm, about 85nm, about 86nm, about 87nm, about 88nm, about 89nm, about 90nm, about 91nm, about 92nm, about 93nm, about 94nm, about 95nm, about 96nm, about 97nm, about 98nm, about 99nm, about 100nm, about 101nm, about 102nm, about 103nm, about 104nm, about 105nm, about 106nm, about 107nm, about 108nm, about 109nm, about 110nm, about 111nm, about 112nm, about 113nm, about 114nm, about 115nm, about 116nm, about 117nm, about 118nm, about 119nm, about 120nm, about 121nm, about 122nm, about 123nm, about 124nm, about 125nm, about 130nm, about 140nm, about 150nm, about 200nm, about 250nm, about 300nm, about 350nm, about 400nm, about 450nm, or about 500 nm.

Typically, when the size of the core of a nanoparticle or aggregate of nanoparticles is measured with an electron microscopy instrument, the size of the core of the nanoparticle or aggregate of nanoparticles, representing a 30% -70% percentile of the population of nanoparticles and aggregates of nanoparticles, is between about 5nm, about 6nm, about 7nm, about 8nm, about 9nm, about 10nm, about 11nm, about 12nm, about 13nm, about 14nm, about 15nm, about 16nm, about 17nm, about 18nm, about 19nm, about 20nm, about 21nm, about 22nm, about 23nm, about 24nm, about 25nm, about 26nm, about 27nm, about 28nm, about 29nm, about 30nm, about 31nm, about 32nm, about 33nm, about 34nm, about 35nm, about 36nm, about 37nm, about 38nm, about 39nm, about 40nm, about 41nm, about 42nm, about 43nm, about 44nm or about 45nm, about 75nm, about 76nm, about 77nm, About 78nm, about 79nm, about 80nm, about 81nm, about 82nm, about 83nm, about 84nm, about 85nm, about 86nm, about 87nm, about 88nm, about 89nm, about 90nm, about 91nm, about 92nm, about 93nm, about 94nm, about 95nm, about 96nm, about 97nm, about 98nm, about 99nm, about 100nm, about 101nm, about 102nm, about 103nm, about 104nm, about 105nm, about 106nm, about 107nm, about 108nm, about 109nm, about 110nm, about 111nm, about 112nm, about 113nm, about 114nm, about 115nm, about 116nm, about 117nm, about 118nm, about 119nm, about 120nm, about 121nm, about 122nm, about 123nm, about 124nm, about 125nm, about 130nm, about 140nm, about 150nm, about 200nm, about 250nm, about 300nm, about 350nm, about 520nm, about 500nm, or between.

Composition of nanoparticles

Nanoparticles made from conductive materials

The nanoparticles prepared from the conductive material are organic nanoparticles or inorganic nanoparticles.

Inorganic nanoparticles prepared from conductive materials are typically prepared with metallic elements having a standard reduction potential E ° value of equal to or higher than about 0.01 (see table 2 "reduction reactions with E ° values more positive than standard hydrogen electrodes", 8-25, Handbook of chemistry and physics (David r.lide; 88 th edition), more preferably equal to or higher than about 0.1, 0.2, 0.3, 0.4 or 0.5, when measured against standard hydrogen electrodes, typically at 25 ℃ and 1atm pressure. Typical metal elements used to prepare the nanoparticles may be selected from Tl, Po, Ag, Pd, Ir, Pt, Au, and mixtures thereof. Preferably, the metal element that can be used as conductor material for preparing the nanoparticles is selected from Ir, Pd, Pt, Au, and mixtures thereof, more preferably from Au, Pt, Pd, and mixtures thereof. Particularly preferred materials are Au and Pt.

Generally, gold nanoparticles exhibit catalytic activity when their size is reduced to a few nanometers (see M.Auffan et al, Nature Nanotechnology2009, 4(10), 634-641: the definition of inorganic nanoparticles from an environmental, health and safety perspective (labor a definition of inorganic nanoparticles from environmental and safety). In order to reduce the surface area to volume ratio and thereby minimize the contribution of the inorganic nanoparticle surface to the catalytic activity, it is preferred that the median largest dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm, typically at least 40nm or at least 45 nm. Interestingly, the inventors found that gold nanoparticles having a median largest dimension of the cores of the nanoparticles or nanoparticle aggregates of the population equal to 45nm and/or a size of between 42nm and 49nm representing 30% -70% of the percentile of the cores of the nanoparticles or nanoparticle aggregates of the population are more effective in preventing/rescuing MPP compared to gold nanoparticles having a median largest dimension of the cores of the nanoparticles of the population equal to 15nm and/or a size of between 14nm and 16nm representing 30% -70% of the percentile of the cores of the nanoparticles or nanoparticle aggregates of the population⁺Induced functional effects on neuronal networks, the tested gold nanoparticles contained the same gold concentration (see examples 9 and 10).

Organic nanoparticles prepared from conductive materials are typically prepared with organic materials having contiguous sp2 hybridized carbon centers (i.e., carbon double bonds or aromatic rings containing heteroatoms, typically N or S, within or outside the aromatic ring) in their structure. Preferred organic materials are selected from polyaniline, polypyrrole, polyacetylene, polythiophene, polycarbazole, polypyrene, poly (3, 4-ethylenedioxythiophene) and/or poly (3, 4-ethylenedioxythiophene) polystyrene sulfonate.

In a particular aspect, when the material is a conductor material as described above, in particular a metallic material, typically a metal with a standard reduction potential E ° above 0.2, or an organic material, typically an organic material having contiguous sp2 hybridized carbon centers in its structure, preferably a metallic material as described above, in particular any of Au, Pt, Pd and any mixtures thereof, the median largest dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm or at least 40nm and preferably below 500nm, for example 45nm, as described above.

Nanoparticles prepared from semiconductor materials

Nanoparticles prepared from semiconductor materials are typically inorganic nanoparticles.

Inorganic nanoparticles are typically prepared with semiconductor materials that exhibit a relatively small energy bandgap (Eg) between their valence and conduction bands. Typically, the semiconductor material has a bandgap Eg below 3.0eV, when measured typically at room temperature (about 25 ℃) (see, e.g., tables 12-77, table 3; Handbook of chemistry and physics; David r. lite; 88 th edition)). In one particular aspect, the material is intrinsic semiconductor material or extrinsic semiconductor material as described further below.

Intrinsic semiconductor materials are generally composed of elements of group IV A of the Mendeleev (Mendeleev) periodic table, such as silicon (Si) or germanium (Ge), mixed compositions of elements of groups III and V of the Mendeleev periodic table, such as AlSb, AlN, GaP, GaN, InP, InN, etc., or mixed compositions of elements of groups II and VI of the Mendeleev periodic table, such as ZnSe, ZnTe, CdTe, etc.

Extrinsic semiconductor material typically comprises or consists of an intrinsic semiconductor prepared with high chemical purity, wherein the intrinsic semiconductor material comprises a dopant. In a particular aspect, when the extrinsic semiconductor material of the nanoparticle or nanoparticle aggregate consists of an element of group IVA of the mendeleev's periodic table, it is doped with a charge carrier selected from Al, B, Ga, In and P. Such extrinsic semiconductor materials may be n-type, in which negative charge carriers predominate, or p-type, in which positive charge carriers predominate. Typical extrinsic p-type semiconductor materials consist of silicon (Si) or germanium (Ge) doped with a charged carrier selected from aluminum (Al), boron (B), gallium (Ga) and indium (In); typical extrinsic P-type semiconductor materials consist of silicon (Si) or germanium (Ge), usually doped with phosphorus (P).

Generally, the band gap energy of semiconductor nanoparticles shows an increase as the size of the nanoparticles decreases below 10nm (see M.Auffan et al, Nature Nanotechnology2009, 4(10), 634-641: the definition of inorganic nanoparticles from an environmental, health and safety perspective (labor a definition of inorganic nanoparticles from an environmental, health and safety standpoint)). To ensure a low surface area/volume ratio of the nanoparticles or nanoparticle aggregates and to maintain their bulk band gap (bulk band gap) below 3.0eV, it is preferred that the median maximum dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm, preferably at least 40 nm.

Thus, In a particular aspect, when the material is a semiconductor material as described above, In particular a semiconductor material having a band gap Eg below 3.0eV, typically a material consisting of an element of group IVA of the mendeleev periodic table, In particular an element of group IVA of the mendeleev periodic table doped with a charge carrier selected from Al, B, Ga, In and P, or a material consisting of a mixed composition of elements of groups III and V of the mendeleev periodic table, or a material consisting of a mixed composition of elements of groups II and VI of the mendeleev periodic table, the median maximum dimension of the core of the nanoparticles or nanoparticle aggregates of the population is at least 30nm or at least 40nm and preferably below 500 nm.

Nanoparticles prepared from insulator materials having a high relative dielectric constant (relative permittivity), i.e. equal to or higher than 200

Has a high relative dielectric constant_ijk(also known as relative permittivity) of or nanoparticles composed of insulator materials are typically prepared with phases having a band gap Eg equal to or higher than 3.0eVTo dielectric constant_ijkA material preparation equal to or higher than 200, the band gap Eg being generally measured at room temperature (about 25 ℃), and the relative dielectric constant_ijkUsually between 20 ℃ and 30 ℃ and at 10²Measured between Hz and infrared frequencies (see, e.g., tables 12-45, "dielectric constant of inorganic solids (dielectric constant)", "Handbook of chemistry and physics"; David R.Lide; 88 th edition; Compilation of electrostatic dielectric constants of inorganic solids (dielectric constant of inorganic solids), K.F.Young and H.P.R.Fredikse.J.Phys.chem.Ref.Data, Vol.2, No. 2, 1973).

Such nanoparticles are generally prepared with a dielectric material, preferably selected from BaTiO₃、PbTiO₃、KTaNbO₃、KTaO₃、SrTiO₃、BaSrTiO₃And the like.

Typically, a perovskite-based structure of PbTiO₃Nanoparticles exhibit a change in their paraelectric-ferroelectric transition temperature at nanoparticle sizes of less than 20nm to 30nm (see M. Auffan et al, Nature Nanotechnology2009, 4(10), 634: definition of inorganic nanoparticles from an environmental, health and safety perspective (health and safety)). In order to ensure a low surface area/volume ratio of the nanoparticles or nanoparticle aggregates and maintain their dielectric properties, it is preferred that the median maximum dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm, typically at least 40 nm.

Thus, in one particular aspect, when the material is as described above having a relatively high dielectric constant equal to or higher than 200_ijkIn particular an insulator material having a band gap Eg equal to or higher than 3.0eV, preferably selected from BaTiO₃、KTaNbO₃、KTaO₃、SrTiO₃And BaSrTiO₃In the mixed metal oxide of (a), the median maximum dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 30nm or at least 40nm and preferably below 500 nm.

Nanoparticles prepared from insulator materials having a low relative dielectric constant (relative permittivity), i.e. equal to or lower than 100

Nanoparticles prepared from or consisting of insulator materials having a low relative permittivity are generally prepared with a band gap Eg equal to or higher than 3.0eV and a relative permittivity_ijkEqual to or lower than 100, preferably lower than 50 or lower than 20, said band gap Eg being generally measured at room temperature (about 25 ℃), and said relative dielectric constant_ijkUsually between 20 ℃ and 30 ℃ and 10²Measured between Hz and infrared frequencies (see, e.g., tables 12-45, "dielectric constant of inorganic solids (dielectric constant)", "Handbook of chemistry and physics"; David R.Lide; 88 th edition; Compilation of electrostatic dielectric constants of inorganic solids (dielectric constant of inorganic solids), K.F.Young and H.P.R.Fredikse.J.Phys.chem.Ref.Data, Vol.2, No. 2, 1973).

Such nanoparticles are typically prepared with a dielectric material selected from the group consisting of metal oxides, mixed metal oxides, the metal elements of which are from period 3, 5 or 6 of the mendeleev's periodic table or are lanthanides, and carbon materials. The dielectric material is preferably selected from Al₂O₃、LaAlO₃、La₂O₃、SiO₂、SnO₂、Ta₂O₅、ReO₂、ZrO₂、HfO₂And carbon diamond. More preferably, the dielectric material is selected from ReO₂、ZrO₂、HfO₂And any mixtures thereof. Particularly preferred is a material selected from ZrO₂And HfO₂The dielectric material of (1). In a particular and preferred aspect, the dielectric material or metal oxide is not CeO₂(cerium oxide), Fe₃O₄(iron oxide), SiO₂(silica) or any mixture thereof.

Zirconium (Zr) and hafnium (Hf) are both 4⁺Elements in the oxidation state, and Zr⁴⁺And Hf⁴⁺Size and combination of elementsThe chemical properties are almost the same; this is why these two ions are considered together when establishing their aqueous chemistry (see chapter 8, section 8.2 Zr4+ and Hf4+ (Zr4+ and Hf4+), page 147 "hydrolysis of cations", Baes C.F.&Mesmer r.e.; john Wiley and Sons, Inc.1986 reprinting).

In a particular aspect, as described above, when the material is selected from ReO₂、ZrO₂、HfO₂Preferably selected from ZrO₂And HfO₂And any mixtures thereof, the median maximum dimension of the cores of the nanoparticles or nanoparticle aggregates of the population is at least 10nm and preferably below 500 nm.

Shape of nanoparticles or nanoparticle aggregates

Since the shape of the particles or aggregates may affect their "biocompatibility", particles or aggregates of very uniform shape are preferred. For pharmacokinetic reasons, nanoparticles or aggregates that are substantially spherical, circular or ovoid in shape are therefore preferred. Such a shape also facilitates interaction of the nanoparticle or aggregate with or uptake by cells. A spherical or round shape is particularly preferred.

The shape of the nanoparticle or nanoparticle aggregate is typically evaluated using electron microscopy, such as Transmission Electron Microscopy (TEM).

Biocompatible coating of nanoparticles or nanoparticle aggregates

In a preferred embodiment, the core of the nanoparticle or nanoparticle aggregate used to prepare the subject composition in the context of the present invention may be coated with a biocompatible material selected from agents exhibiting stealth properties. The agent exhibiting stealth properties may be an agent exhibiting a steric group. Such groups may be selected from, for example, polyacrylates; polyacrylamide (poly (N-isopropylacrylamide)); polyamides (polycarboamides); a biopolymer; polysaccharides such as dextran or xylan; and collagen. In another preferred embodiment, the core of the nanoparticle or nanoparticle aggregate may be coated with a biocompatible material selected from agents that allow interaction with biological targets. Such agents may generally carry a positive or negative charge on the surface of the nanoparticle or nanoparticle aggregate. The agent that forms a positive charge on the surface of the nanoparticle or nanoparticle aggregate can be, for example, aminopropyltriethoxysilane or polylysine. The agent forming a negative charge on the surface of the nanoparticle or nanoparticle aggregate may be, for example, phosphoric acid (salt) (e.g., polyphosphoric acid (salt), metaphosphoric acid (salt), pyrophosphoric acid (salt), etc.), carboxylic acid (salt) (e.g., citric acid (salt) or dicarboxylic acid, particularly succinic acid), or sulfuric acid (salt).

In a preferred embodiment, the core of the nanoparticles or nanoparticle aggregates used in the context of the present invention exhibits a hydrophilic neutral surface charge or is coated with a biocompatible material (i.e. a coating agent) selected from hydrophilic agents that impart a neutral surface charge to the nanoparticles. Indeed, when the nanoparticles of the present invention are administered to a subject, the core of the nanoparticles exhibiting a hydrophilic neutral surface charge or of the nanoparticles coated with a biocompatible agent selected from hydrophilic agents that impart a neutral surface charge to the nanoparticles is particularly advantageous for optimizing the use of the nanoparticles described herein in the treatment of neurological diseases.

The hydrophilic agent that imparts a neutral surface charge to the core of the nanoparticle or nanoparticle aggregate may be an agent that exhibits a functional group selected from the group consisting of alcohol (R-OH), aldehyde (R-COH), ketone (R-CO-R), ester (R-COOR), acid (R-COOH), thiol (R-SH), sugar (e.g., glucose, fructose, ribose), acid anhydride (RCOOOC-R), and pyrrole. The hydrophilic agent that imparts a neutral surface charge to the core of the nanoparticle or aggregate of nanoparticles may be a monomer, dimer, oligomer, polymer, or copolymer. When the reagent is an oligomer, it may be an oligosaccharide, for example a cyclodextrin. When the agent is a polymer, it may be a polyester (e.g. poly (lactic acid) or polyhydroxyalkanoic acid), a polyether, polyethylene oxide, polyethylene glycol, polyvinyl alcohol, polycaprolactone, polyvinylpyrrolidone, a polysaccharide such as cellulose, polypyrrole, or the like.

In addition, the hydrophilic agent that imparts a neutral surface charge to the core of the nanoparticle or nanoparticle aggregate may be an agent that exhibits a specific group (R-) capable of interacting with the surface of the nanoparticle or nanoparticle aggregate. R is typically selected from thiol, silane, carboxyl and phosphate groups.

When the core of the nanoparticle or nanoparticle aggregate is a conductor or semiconductor and metal nanoparticle, R is preferably a thiol, thioether, thioester, dithiolane or carboxyl group. Preferably, the hydrophilic neutral capping agent is selected from the group consisting of thioglucose, 2-mercaptoethanol, 1-thioglycerol, thiodiglycol and hydroxybutyric acid.

When the core of the nanoparticle or nanoparticle aggregate is an insulator, and an oxide or mixed oxide nanoparticle, R is preferably a silane or phosphate group. Preferably, the hydrophilic neutral coating agent is hydroxymethyl triethoxysilane, fructose-6-phosphate or a glucose-6-phosphate compound.

The hydrophilic agent that imparts a neutral surface charge to the core of the nanoparticle or aggregate of nanoparticles may be a zwitterionic compound, such as an amino acid, peptide, polypeptide, vitamin, or phospholipid.

As is well known to those skilled in the art, the surface charge of a nanoparticle or nanoparticle aggregate is typically measured by zeta potential, typically determined in water (solution) at a concentration of the nanoparticle or nanoparticle aggregate material of between 0.01 and 10g/L, a pH of between 6 and 8, and a concentration of the electrolyte (in water) of typically between 0.001 and 0.2M, for example 0.01M or 0.15M. The surface charge of the nanoparticle or aggregate of nanoparticles is typically between-10 mV and +10mV (corresponding to a neutral surface charge), -20mV and +20mV, or-35 mV and +35mV, under the conditions defined above. When neutral, the surface charge of the nanoparticle or aggregate of nanoparticles is typically between-10 mV, -9mV, -8mV, -7mV, -6mV, -5mV, -4mV, -3mV, -2mV, or-1 mV and 1mV, 2mV, 3mV, 4mV, 5mV, 6mV, 7mV, 8mV, 9mV, or 10 mV. When negative, the surface charge of the nanoparticle or aggregate of nanoparticles is typically less than-11 mV, -12mV, -13mV, -14mV-15mV, -16mV, -17mV, -18mV, -19mV, -20mV, -21mV, -22mV, -23mV, -24mV, -25mV, -26mV, -27mV, -28mV, -29mV, -30mV, -31mV, -32mV, -33mV, -34mV, or-35 mV.

A biocompatible full coating of the nanoparticles or aggregates may be advantageous in the context of the present invention in order to avoid any charge on the surface of the nanoparticles when the nanoparticles exhibit a hydrophilic neutral surface charge. By "fully coated" is meant the presence of a very high density/compactness of biocompatible molecules capable of producing at least a complete monolayer on the surface of the particle.

The biocompatible coating allows in particular the stability of the nanoparticles in fluids, such as physiological fluids (blood, plasma, serum, etc.) or any isotonic or physiological medium required for drug administration.

Stability can be confirmed by dry extract quantification using a drying oven and measured on the nanoparticle suspension before and after filtration, which is typically performed on a 0.45 μm filter.

Advantageously, the coating maintains the in vivo integrity of the particle, ensures or improves its biocompatibility, and facilitates its optional functionalization (e.g., with spacer molecules, biocompatible polymers, targeting agents, proteins, etc.).

The biocompatible nanoparticles or nanoparticle aggregates of the invention should neither dissolve and release toxic substances after in vivo administration (i.e. at physiological pH) nor exhibit redox behavior, and are generally safe for use in said nanoparticles or nanoparticle aggregates which are considered biocompatible, i.e. in a subject, in particular a mammal, preferably a human.

Another particular object described herein relates to compositions, in particular pharmaceutical compositions, comprising nanoparticles and/or nanoparticle aggregates, such as defined above, preferably together with a pharmaceutically acceptable carrier or medium.

In particular, described herein is a composition for preventing or treating a neurological disease or at least one symptom thereof as described herein in a subject without exposing the nanoparticles or nanoparticle aggregates to an electric field, and preferably without exposing the nanoparticles or nanoparticle aggregates to an electric fieldExposed to any other external activation source such as a light source, a magnetic field or an ultrasound source, wherein the composition comprises or consists of nanoparticles and/or nanoparticle aggregates and a pharmaceutically acceptable carrier, and wherein the material of the nanoparticles or nanoparticle aggregates is typically selected from the group consisting of conductor materials, semiconductor materials, dielectric constant materials as described and explained above_ijkInsulator material of 200 or more, and dielectric constant_ijkInsulator material equal to or lower than 100.

In a preferred aspect, the composition comprises or consists of at least two different nanoparticles and/or nanoparticle aggregates, each nanoparticle or nanoparticle aggregate consisting of a different material, typically selected from the group consisting of conductor materials, semiconductor materials, dielectric constant materials_ijkInsulator material of 200 or more, and dielectric constant_ijkInsulator material equal to or lower than 100.

In a typical aspect of the invention, the nanoparticles or nanoparticle aggregates described herein are not used as carriers for (active) therapeutic compounds or drugs.

In a particular aspect, the composition can comprise a nanoparticle or aggregate of nanoparticles of the invention and a therapeutic agent. In the context of the present invention, such therapeutic agents are generally neither nanoparticles nor nanoparticle aggregates. The therapeutic agent may be selected from any drug used in the treatment of neurological disorders. The therapeutic agent is typically selected from the group consisting of antipsychotics, anti-dopaminergic agents, anticholinergics, cholinergics, anti-glutamatergic agents, acetylcholinesterase inhibitors, N-methyl D-aspartate (NMDA) receptor antagonists, gamma-aminobutyric acid (GABA) agonists, botulinum toxins, dystonia agents, antiepileptics, anticonvulsants, mood stabilizers, antidepressants, and sedatives.

The composition may be in the form of a solid, liquid (suspended particles), aerosol, gel, paste, or the like. Preferred compositions are in liquid or gel form. Particularly preferred compositions are in liquid form.

The pharmaceutically acceptable carrier or vehicle employed can be any of the classical carriers to the skilled artisan, such as saline, isotonic, sterile, buffered solutions, solutions in non-aqueous media, and the like.

The composition may also include stabilizers, sweeteners, surfactants, polymers, and the like.

It can be formulated, for example, into ampoules, aerosols, bottles, tablets, capsules, by using pharmaceutical formulation techniques known to the skilled worker.

The nanoparticles or nanoparticle aggregates of the invention may be administered to a subject using different possible routes, e.g. intracranial, Intravenous (IV), airway (inhalation), intrathecal, intraocular or buccal (oral), Intracerebroventricular (ICV), preferably using intracranial or intrathecal.

Repeated injections or administrations of the nanoparticles may be performed as appropriate. Preferably, the nanoparticle or nanoparticle aggregate is administered once.

The nanoparticles and/or nanoparticle aggregates, once administered, typically interact with the neuronal subject. In a preferred aspect, the interaction is a long-term interaction, i.e., an interaction of hours, days, weeks, or months. In a particular aspect, the nanoparticles or nanoparticle aggregates are left in the subject.

The nanoparticles or nanoparticle aggregates and compositions comprising such nanoparticles or nanoparticle aggregates described herein are for use in a subject, typically in an animal, preferably a mammal, more preferably in a human, typically a human patient, regardless of age or sex.

The typical amount of nanoparticles or nanoparticle aggregates administered in the cerebral cortex, hippocampus and/or amygdala of a subject is in the range of 10⁵And 10¹⁷Between 10⁵And 10¹⁶Between or at 10⁵And 10¹⁵Preferably between 10⁷And 10¹⁴More preferably between 10⁹And 10¹²In the meantime. And, in the large of the objectTypical amounts of nanoparticles or nanoparticle aggregates administered in the cerebral cortex, hippocampus and/or amygdala are in the range of 10²And 10¹²Nanoparticles or nanoparticle aggregates/cm³In the meantime.

Typical amounts of nanoparticles or nanoparticle aggregates administered in the deep brain of a subject are in the range of 10⁴And 10¹⁷Between 10⁴And 10¹⁶Between 10⁴And 10¹⁵Between or at 10⁴And 10¹⁴Preferably between 10⁶And 10¹²More preferably between 10⁸And 10¹¹In the meantime. And, a typical amount of nanoparticles or nanoparticle aggregates administered in the deep brain of a subject is at 10¹And 10¹¹Nanoparticles or nanoparticle aggregates/cm³In the meantime.

Also described herein is a method of preventing or treating a neurological disease or at least one symptom thereof in a subject, wherein the method comprises the step of administering to the subject any one of the nanoparticles or nanoparticle aggregates described herein. Such a method typically does not comprise any step of exposing the object, more precisely the nanoparticles or nanoparticle aggregates that have been applied to the object, to an electric field, and preferably also does not comprise any step of exposing the object, more precisely the nanoparticles or nanoparticle aggregates that have been applied to the object, to any other external activation source, such as a light source, a magnetic field or an ultrasound source.

Another object described herein relates to a kit comprising or consisting of at least two different nanoparticles and/or at least two different aggregates of nanoparticles as described herein, each nanoparticle or aggregate of nanoparticles being made of a material generally selected from the group consisting of conductor materials, semiconductor materials, dielectric constants as described herein_ijkInsulator material of 200 or more, and dielectric constant_ijkA different material composition of the insulator material equal to or lower than 100.

In a particular embodiment, the kit comprises in different containers different nanoparticles and/or aggregates of nanoparticles as described herein (which are defined as being contacted, typically mixed, in situ, i.e. at a target site, or in vitro or ex vivo, and then depositing the mixture at the target site).

Another object relates to a kit further comprising at least one additional therapeutic agent different from the nanoparticle or nanoparticle aggregate as described herein, such as an antipsychotic, an anti-dopaminergic agent, a dopaminergic agent, an anticholinergic agent, a cholinergic agent, an anti-glutamatergic agent, a glutamatergic agent, an acetylcholinesterase inhibitor, an N-methyl D-aspartate (NMDA) receptor antagonist, a gamma-aminobutyric acid (GABA) agonist, a botulinum toxin, an anti-dystonia agent, an antiepileptic drug, an anticonvulsant, a mood stabilizer, an antidepressant and a sedative agent, which the skilled person is able to select depending on the nature of the disease to be targeted. As explained above, such additional therapeutic agents are typically neither nanoparticles nor nanoparticle aggregates.

Also described herein is the in vivo, in vitro or ex vivo use of such a kit in a method of preventing or treating a neurological disease as described herein or at least one symptom thereof in a subject without exposing the nanoparticles or nanoparticle aggregates administered to said subject to an electric field and preferably without exposing it to any other external activation source, such as a light source, a magnetic field or an ultrasound source. Also described herein is a kit as described herein for use in preventing or treating a neurological disease or at least one symptom thereof in a subject without exposing the nanoparticles or nanoparticle aggregates administered to the subject to an electric field, and preferably without exposing it to any other external activation source, such as a light source, a magnetic field, or an ultrasound source.

At the neuronal level, nanoparticles have been described to increase or inhibit electrical excitability of neurons. For example, zinc oxide, carbon nanotubes and gold nanoparticles have been found to increase electrical excitability of neurons, while copper oxide, silver, carbon black, iron oxide and titanium oxide have been found to inhibit electrical excitability of neurons (Polak P & Shefi O. Nanomedicine: Nanotechnology, Biology and Medicine 11(2015) 1467. 1479, nanoscale agents in neuroscience services: the use of nanoparticles for manipulating neuronal growth and activity (nanoparticles of neural growth and activity).

Studies of the systemic effects of silver nanoparticles coated with amphiphilic polyethylene glycol (cAgNP) - [ cAgNP hydrodynamic diameter in pure water 13nm ± 2nm (dynamic light scattering technique), zeta potential-69 mv (zetasizer nano) ], on the neuronal system showed that the nanoparticles induced changes in the mechanisms affecting excitability. In addition, neuronal network simulations show that local cAgNP-induced changes lead to changes in network activity throughout the network, indicating that local application of cAgNP can affect the activity throughout the network (Busse M. et al International Journal of Nanomedicine2013: 83559-3572, estimating the modulating effect of nanoparticles on neuronal circuits using computational amplification).

Also, it has been described that increased neuronal excitability associated with Intracellular nanoparticles may have deleterious effects on neurons under pathological conditions such as seizures (Jung S et al PLOS ONE 2014, 9(3) e91360, Intracellular nanoparticles increase neuronal excitability and exacerbate seizure activity in mouse brain (Intracellular mineral involvement in seizure activity).

The nanoparticles or nanoparticle aggregates of the invention are used for preventing or treating a neurological disease or at least one symptom thereof by normalizing the synchronization of oscillations within and/or between neuronal networks within and/or between different regions of the brain without exposing said nanoparticles or nanoparticle aggregates to an electric field, and preferably without exposing them to any other external activation source, such as a light source, a magnetic field or an ultrasound source.

As shown in fig. 2 and 3, in neurological diseases, communication within and/or between different regions of the brain is affected. Depending on the neurological disorder and related symptoms, exposing specific areas of the brain to the nanoparticles of the present invention will improve communication by normalizing the synchronization of oscillations within and/or between neuronal networks within and/or between different areas of the brain (i.e., normalization of coherence) (fig. 4 and 5).

The following examples and their corresponding figures illustrate the invention without limiting its scope.

Drawings

FIG. 1 is a schematic representation of the brain (sagittal plane).

FIG. 2. supersynchronization and impaired synchronization between two neural networks.

Figure 3 brain regions involved in various neurological diseases.

Figure 4 effect of Nanoparticles (NPs) on the normalization of hypersynchrony (dyskinesias).

Figure 5 effect of Nanoparticles (NPs) on normalization of synchronization impairment (mental and cognitive disorders).

FIG. 6 illustrates the use of MPP⁺Protocol for treatment-induced parkinson's disease and electrical activity recordings.

Mouse ventral midbrain/cortex co-cultures were prepared from E14.5NMRI mice and cultured on 48-well MEA for 3 weeks (total culture period). After 7 days of culture (day 7), suspensions of nanoparticles ("nanoparticle" group), GDNF (20ng/ml) ("reference" group) or water ("control" group and "MPP" group)⁺"group") and MPP on day 8⁺(20. mu.M) ("nanoparticles" group, "reference" group, and "MPP⁺"group") or water ("control" group). Spontaneous activity was recorded on day 21.

Figure 7. a scheme of two simplified bursts outlines some parameters that can be extracted from the electrical activity record. Parameters describing the general activity (spike), burst (burst), burst interval (IBI) and burst period) and burst structure (burst duration, burst plateau, burst amplitude, burst peak potential interval (ISI) and burst area) are indicated. The Standard Deviation (SD) of these parameters is a measure of the regularity of the general activity and burst structure, respectively. Coefficient of variation with time (CV)_{Time of day}) Reflecting the temporal regularity of the activity pattern of each unit. CV of_{Time of day}Calculated from the ratio of the standard deviation and the mean of the parameters. NetworkCoefficient of Variation (CV) between_Network) Reflecting the synchronization between neurons within the network. CV of_NetworkCalculated by the ratio of the standard deviation to the mean of the parameters on the network. Large CV of_NetworkThe values imply a wide range of activity variation across the network, meaning that synchronization is low.

FIG. 8 shows the comparison between the "nanoparticles" group (nanoparticles from examples 1 and 2) and the "reference" group and the "control" group and the "MPP⁺"functional effects on activity of the midbrain/cortical network observed in group comparisons. Data show MPP⁺Induced functional effects and demonstrated the prevention/rescue efficacy provided by the nanoparticles of the invention or by GDNF (i.e., the ability to prevent/rescue functional effects to a similar level as in the "control" group).

FIG. 9 comparison of the "nanoparticles" group (nanoparticles from examples 5 and 6) with the "control" group and "MPP⁺"functional effects on activity of the midbrain/cortical network observed in group comparisons. Data show MPP⁺Induced functional effects and demonstrates the prevention/rescue efficacy provided by the nanoparticles of the invention (i.e., the ability to prevent/rescue functional effects to a similar level as the "control" group).

FIG. 10 for the "nanoparticles" group, "reference" group, "control" group, and "MPP⁺"analysis of group Effect scores.

FIG. 11. Experimental protocol, treatment and electrical activity recording for the induction of Alzheimer's disease with amyloid beta 1-42(A β 1-42). After 4 weeks of culture (incubation period), Α β 1-42(100nM) ("nanoparticles" group, "reference" group and "Α β" group) or water ("control" group) (T0) were added to the neuronal network. Four (4) hours later, nanoparticle suspension ("nanoparticle" group), Donepezil (300nM) ("reference" group), or water ("control" group and "a β" group) was added. Spontaneous activity was recorded as follows:

- - -T0 (before addition of Abeta 1-42)

-T0+1h, +2h, +3h, +4h (before addition of nanoparticles, donepezil or water), +5h and +6 h.

FIG. 12 functional effects on cortical network activity observed in the "nanoparticles" and "reference" groups compared to the "control" and "A β 1-42" groups. The data show the a β 1-42 functional effect and demonstrate the rescue efficacy (i.e., the ability to rescue the functional effect to a similar level as the "control" group) provided by the nanoparticles of the present invention or by donepezil.

Figure 13 effect score analysis for the "nanoparticles" group, the "reference" group, the "control" group (effect score 0) and the "Α β" group (effect score 1).

FIG. 14 is a representative TEM image of GOLD nanoparticles from example 9, the median largest dimension of the cores of the nanoparticles of the population being equal to 108nm (GOLD-110), 83nm (GOLD-80), 45nm (GOLD-45), 34nm (GOLD-30), and 15nm (GOLD-15), respectively.

Figure 15. control (effect score of 0) and "MPP" for the "nanoparticles" group (GOLD-45 and GOLD-15 nanoparticles from example 9), the "control" group⁺Effect score analysis for "group (effect score ═ 1).

Figure 16. representative Scanning Electron Microscopy (SEM) images of PEDOT nanoparticles from example 11.

Figure 17. pair of "nanoparticles" group (PEDOT nanoparticles from example 11), "control" group (effect score 0) and "MPP ═ MPP⁺Effect score analysis for "group (effect score ═ 1).

Examples

In vitro study of neurons

At the neuronal level, the patch-clamp technique is very useful for detecting action potentials, since it allows direct measurement and control of the membrane potential of neurons at the same time.

This technique was used to evaluate the effect of nanoparticles on individual neurons.

In vitro study of neuronal networks

Distributed neuronal cultures coupled with a multi-electrode array (MEA) are widely used to better understand the complexity of brain networks. In addition, the use of discrete neuron assemblies allows for manipulation and control of the connectivity of the network. The MEA system enables non-invasive, durable, non-invasive, and non-invasive delivery of a signal from multiple sites in a neural network in real time,Simultaneous extracellular recording increases spatial resolution, thereby providing a robust measure of network activity. The simultaneous collection of action potential and field potential data over a long period of time allows monitoring of network functions resulting from the interaction of all cellular mechanisms responsible for spatio-temporal pattern generation (Johnstone A.F.M. et al, neurobiology, 2010, 31, 331-^stcentury)). In contrast to patch clamp and other single electrode recording techniques, MEA measures the response of the entire network, integrating the overall information of all receptor, synapse and neuron type interactions present in the network (Novellino A. et al, front ties in Neuroengineering, 2011, 4(4), 1-14: Development of microelectrode array-based neurotoxicity tests: evaluation of laboratory reproducibility with neuroactive chemicals: assessment of laboratory reproducibility with neuroactive chemicals). Thus, MEA recordings have been used to understand neuronal communication, information coding, dissemination and processing in neuronal cultures (Taketani, M. and Baudry, M. (2006.) Advances in Network Electrophysiology (Advances in Network Electrophysiology) New York, NY: Springer; Obien et al, Frontiers in Neurosciences, 2015, 8 (423): Revealing neuronal function by microelectrode array recordings). MEA technology is a complex phenotypic high-content screen for characterizing functional changes in network activity in electroactive cell cultures and is very sensitive to neurogenesis as well as neural regeneration and neurodegeneration. Furthermore, neuronal networks grown on MEA are known to respond to neuroactive or neurotoxic compounds in approximately the same concentration range that alters intact mammalian nervous system function (Xia et al, Alcohol, 2003, 30, 167-174: tissue-type electrophysiological responses of cultured neuronal networks to ethanol (Histiotic electrophysiological responses of clinical neural networks to ethanol); Gramowski et al, European Journal of Neuroscience, 2006, 24, 455-465: functional screening of traditional antidepressants (Functional screening of traditional antidepressant networks) with primary cortical neuronal networks grown on multi-electrode neural chips; gramowski et al, Frontiers in Neurology, 2015, 6 (158): enhancing cortical network activity in vitro and promoting GABA-ergic neurogenesis by 150MHz carrier electromagnetic field stimulation pulsed with alternating10and 16Hz modulation (Enhancement of physiological network activity in vitro and stimulation of GABAergic neurogenesis by stimulation with an electromagnetic field of electromagnetic field with 150MHz carrier wave pulsed with an alternating10and 16Hz modulation)).

This technique was used to evaluate the effect of nanoparticles on neuronal networks.

In vivo study of neuronal networks

The effect of the nanoparticles of the invention on the neuronal network of an animal is evaluated taking into account an appropriate animal model.

For example, a mouse model of parkinson's disease is used to assess the effect of nanoparticles on mitigating behavioral impairment (dyskinesias). In addition, rat or mouse models of alzheimer's disease are used to evaluate the effect of nanoparticles on spatial learning and memory dysfunction (cognitive impairment) in animals.