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Recent Patents on Drug Delivery & Formulation 2012, 6, 2-18

Advances in the Treatment of Neurodegenerative Disorders Employing Nanoparticles


Carlos Spuch1*, Ortolano Saida1 and Carmen Navarro1
1

Department of Pathology and Neuropathology, University Hospital of Vigo, Spain

Received: November 3, 2011; Accepted: December 6, 2011; Revised: November 30, 2011

Abstract: Nanoparticles could potentially revolutionise treatment for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and strokes. Nanotechnologies hold great promise in brain therapy as they protect the therapeutic agent and allow its sustained release; the nanoparticles can be used as gene delivery vehicles. The application of neurotrophic factors is able to modulate neuronal survival and synaptic connectivity and it is a promising therapeutic approach for many neurodegenerative diseases, however, due to limitations posed by the restrictive blood brain barrier (BBB), it is very difficult to ensure long-term administration in the brain. Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system (CNS). New therapeutics with the capacity to cross the BBB is critically needed for treatment of these diseases. In recent years, nanotechnology had patented new formulations and has evolved as a new treatment for brain diseases, especially for neurodegenerative diseases, where genetically engineered cells can be used to deliver specific growth factors to target cells. Overall, the aim of this review is to summarize the last patents, clinical trials and news related with nanoparticles technology for the treatment of neurodegenerative diseases.

Keywords: Alzheimers disease, blood brain barrier, brain, central nervous system, drug delivery, nanotechnology, nanoparticles, neurodegenerative diseases, Parkinsons disease, prion diseases, therapeutics. NEURODEGENERATIVE DISEASES Neurodegenerative diseases are some of the most debilitating disorders, affecting thinking, skilled movements, feelings, cognitive and memory. Nowadays neurodegenerative diseases are the fourth leading cause of death in the developed world after heart diseases, cancer and stroke [1]. Each year, over 10 million people globally suffer from neurodegenerative diseases. This figure is expected to grow by 20% over the next decade as the aging population increases and lives longer. Many similarities appear that relate these diseases to each other on a sub-cellular and molecular levels [2]. Discovering these similarities and signalling pathways could offer hope for therapeutic advances that ameliorate many diseases simultaneously. The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. Only within the group of neurodegenerative disease includes serious disorders such as AD, PD, Lewy body dementia (LBD), frontotemporal dementia
*Address correspondence to this author at the Department of Pathology and Neuropathology, University Hospital of Vigo, Hospital of Meixoeiro, Meixoeiro s/n, 36215, Vigo, Spain; Tel: +34 986814585; Fax: +34 986276416; E-mail1: carlos.spuch@gmail.com; 2: carlos.spuch.calvar@sergas.es

(FTD), Vascular dementia (VD) and some rare disorders such as amyotrophic lateral sclerosis (ALS), Huntington disease (HD), spinocerebellar ataxia and prion diseases [3]. Despite the important differences in clinical manifestation, neurodegenerative disorders share common features such as their appearance late in life, the extensive neuronal loss and synaptic abnormalities, and the presence of cerebral deposits of misfolded proteins aggregates [3]. Approximately 24 million people worldwide suffer from dementia, 60% of cases being due to AD, which occurs in 1% of individuals aged 50 to 70 and dramatically increases to 50% for those over 70 years [4]. Dramatically, these numbers are estimated to increase to 15 million in the next 40 years [5]. AD is a chronic and progressive neurodegenerative disorder and the most cause of dementia in the elderly. It is typified clinically by learning and memory impairment and pathologically by gross cerebral atrophy, indicative of neuronal loss, with numerous extracellular neuritic amyloid plaques and intracellular neurofibrillary tangles found predominantly in the frontal and temporal lobes, including the hippocampus [6]. Although the mechanisms underlying AD are not completely clear yet several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide are the most advanced [7]. In AD there are two types of protein deposits: amyloid plaques are deposited extracellularly in the brain parenchyma and around the cerebral vessels walls and their main component is a 1-40 and 1-42 residues peptide termed beta-amyloid protein [8, 9].

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2012 Bentham Science Publishers

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It is well established that innocuous monomers of amyloid beta become neurotoxic upon aggregation [10] and the toxicity of amyloid beta involved self aggregation of monomers into oligomers and higher aggregated forms [11]. Amyloid plaques in the human AD brain are known to contain a heterogeneous mixture of amyloid beta peptides [12]. In addition to main amyloid beta species (1-40 and 1-42), a variety of post-transcriptionally modified variants have been identified [13]. The predominant accumulation and initial peptide deposited in the brain parenchyma is a highly fibrillogenic amyloid-beta 1-42 [9]. Targeting amyloid-beta 1-42 in all its aggregation forms has been suggested for therapeutic and diagnostic purposes [14, 15]. Moreover, it has been recently demonstrated that brain and blood amyloid-beta are in equilibrium through the BBB, and sequestration of amyloid-beta in the blood may shift this equilibrium, drawing out the excess from the brain [16-18]. PD is also a chronic and progressive movement disorder that involves the malfunction of dopaminergic neurons. It is not fatal but it gets worse over time. The symptoms of the disease include tremors, stiffness and slow or hesitant speech. PD is characterized by massive depletion of striatal dopamine as a result of degeneration of dopaminergic neurons in the substantia nigra pars compacta. Besides the lack of dopamine at the cellular level may appear the formation of Lewy bodies in the substantia nigra, which are cytoplasmic inclusions composed of fibrils, ubiquitin and alpha-synuclein [19, 20]. Worldwide, there are an estimated 7-10 million people living with PD. Unfortunately, many people with PD will develop a mild form of dementia, with slowed though processes, memory problems, difficulty concentrating, apathy and poor motivation, word-finding difficulty with complicated tasks or tasks involving visual space. Actually there are almost 1.2 million people suffering from PD in Europe and over 1 million in US, however, medication only provides patients with temporary symptomatic relief, while access to care and treatment differs widely depending on where patients live [21]. LBD is the second most common type of progressive dementia after AD, causes a progressive decline in mental abilities. LBD is characterized by fluctuations in cognition with variations in attention and alertness, recurrent formed visual hallucinations, visual spatial dysfunction and, like PD; LBD can result in rigid muscles, slowed movement and tremors [22]. Despite the heterogeneity of their clinical phenotypes, a significant neuropathological overlap is observed among AD, PD and LBD. The hallmark histological lesion is the presence of Lewy bodies and Lewy neurites. Variation in the distribution of Lewy body pathology is present among LBD, with more neocortical and limbic system Lewy bodies in both [23]. LBD overlaps clinically with AD and PD, but is more associated with the latter. With LBD, the loss of cholinergic neurons is thought to account for the degradation of cognitive functioning, as in AD; while the loss of dopaminergic neurons is thought to account for the degradation of motor control, as in PD. Thus, LBD is similar in some ways to both the dementia resulting from AD and PD. The overlap of neuropathologies and presenting symptoms (cognitive, emotional, and motor) can make an accurate differential diagno-

sis difficult. In fact, it is often confused in its early stages with AD or VD, the main difference is that AD usually begins quite gradually and LBD often has a rapid and acute onset, with especially rapid decline in the first few months. Current estimates are that about 60 to 75% of diagnosed dementias are of the AD and 10 to 15% are LBD [24]. FTD is a clinical syndrome associated with shrinking of the frontal and temporal anterior lobes of the brain. The current designation of the syndrome groups together Picks disease, primary progressive aphasia, and semantic dementia as FTD. As it is defined today, the symptoms of FTD fall into two clinical patterns that involve either: changes in behaviour and problems with language. The first symptoms often involve changes in personality, judgment, planning and social functioning. Individuals may make rude or off-colour remarks to family or strangers. They may show apathy and loss of interest or excessive happiness and excitement. Individuals may have a strong desire to eat and gain weight as a result [25]. FTD affects parts of the brain containing microscopic Pick bodies; abnormal protein-filled structures that develop within neurons. The histological features of FTD are the presence of neurofibrillary tangles of phosphor-Tau in the brain [26]. Also, a variety of mutations on several different genes have been linked to specific subtypes of FTD such as MAPT, PGRN, FUS or VCP genes [27]. But more than half the people who develop FTD have no family history of dementia. FTD is often misdiagnosed as a psychiatric problem or as AD, but FTD tends to occur at a younger age than does AD, typically between the ages 40 and 70 [28]. VD is widely considered the second most common type of dementia. It is a distinct type of dementia with spectrum of specific clinical and pathophysiological features. However, in a very large majority of cases, these alterations occur in an already aged brain, characterized by a milieu of cellular and molecular events common for different neurodegenerative diseases. VD develops when impaired blood flow to parts of the brain deprives cells of food and oxygen. The diagnosis may be clearest when symptoms appear soon after a single major stroke blocks a large blood vessel and disrupts the blood supply to a significant portion of the brain. This situation is sometimes called post-stroke dementia. Symptoms of VD can vary, depending on the specific brain areas deprived of blood. Impairment may occur in steps, where there is a fairly sudden, noticeable change in function, rather than the slow, steady decline usually seen in AD. Memory problems may or may not be a prominent symptom, depending on whether brain regions important in memory are affected [29]. Other rare neurodegenerative diseases with a much lower incidence but equally serious are: ALS is a form of motor neuron disease caused by the degeneration of neurons located in the ventral horn of the spinal cord and the cortical neurons that provide their afferent input. This disorder is characterized by rapidly progressive weakness, muscle atrophy and fasciculation, spasticity and respiratory compromise [30]. HD is a rare fatal brain disorder caused by inherited changes in a single gene called huntingtin (Htt). The

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disease is caused by an autosomal dominant mutation on either of an individual's two copies of the gene. It is the most common genetic cause of abnormal involuntary writhing movements called chorea. These changes lead to destruction of neurons in certain brain regions [31]. Spinocerebellar ataxia is an inherited disorder of brain function. It is characterized by increasing problems with coordination that often affect the legs, hands and speech. There are more than 20 types of spinocerebellar ataxia that have been described [32]. All types of spinocerebellar ataxia are characterized by a progressive incoordination of walking. In addition, they are often associated with poor coordination of hand movements, eye movements, and speech. With some exceptions, the onset of symptoms usually occurs after the age of 18. Spinocerebellar ataxia is slowly progressive, which means that symptoms of the condition gradually worsen over a period of years. Some types of spinocerebellar ataxia can progress more rapidly than others. Brain scans such as magnetic resonance imaging (MRI) and computerized tomography (CT) of affected persons often show shrinkage or atrophy of the cerebellum that becomes more noticeable as the disease progresses [33]. Prion diseases are conformational neurodegenerative disorders characterized by the structural modification of the normal cellular prion protein (PrPC) into a pathological conformer, scrapie prion protein (PrPSc) [34]. They are a unique category of illness in that they can be inherited, infectious or sporadic in occurrence. Thus, the conversion of PrPC to PrPSc can be related to an exogenous infectious source of PrPSc, a mutation in the prion protein that predisposes to such a conformational change or a spontaneous conformational change, as occurs in sporadic prion disease. A comprehensive body of evidence has presented compelling data that the transmissiOverview of nanoparticles and their applications.

ble pathogen for these diseases is a proteinaceous infectious particle (hence the term prion). These spontaneous disorders in humans are very rare, affecting only about one person per million worldwide each year. However, transmissible prion proteins can reach epidemic proportions, as was seen in the UK. Currently, there is no effective therapy for this group of diseases [35].

NANOPARTICLES TECHNOLOGY AS THERAPEUTIC CHALLENGES FOR NEURODEGENERATIVE DISEASES Recent years have witnessed unprecedented growth of research and applications in the area of nanotechnology. There is increasing optimism that nanotechnology, as applied to biomedicine, will bring significant advances in the diagnosis and treatment of disease. Anticipated applications in medicine include drug delivery, diagnostics and production of improved biocompatible materials [18, 36-38] Table 1. The advent of nanotechnology can provide a solution to overcome the future diagnostic and new neurotherapeutic challenges for neurodegenerative diseases as frequent as AD, PD, FTD, HD, etc. Nanoparticles are solid colloidal matrix-like particles made of polymers or lipids, generally administered by intravenous route like liposomes. This technology employs engineered materials with the smallest functional organization on the nanometre scale that are able to interact with biological systems at the molecular level. Nanotechnology employs engineered materials or devices with the smallest functional organization on the nanometre scale (1-100nm) that are able to interact with biological systems at the molecular level. Engineered nanoparticles are an important tool to realize a number of these applications. It has to be recognized that not all particles used for medical purposes comply with the recently proposed and now generally accepted definition of a

Table 1.

Particle Class

Materials Chitosan Dextrane Gelatine

Application Drug and gene delivery Drug and gene delivery Drug and gene delivery Drug and gene delivery Drug and gene delivery Drug and gene delivery Drug delivery Photodynamics and drug delivery Imaging by MRI Imaging by MRI Imaging and diagnostic

Natural materials Alginates Liposomes Starch Dendrimers Fullerenes Ferrofluids USPIONS Quantum dlots Cd/Zn selenides Branched polymers Carbon based carriers SPIONS

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size 100nm. However, this does not necessarily has an impact on their functionality in medical applications. The reason why these nanoparticles are attractive for medical purposes is based on their important and unique features, such as their surface to mass ratio that is much larger than that of other particles, their quantum properties and their ability to adsorb and carry other compounds. Nanoparticles have a relatively large (functional) surface which is able to bind, adsorb and carry other compounds such as drugs, probes and proteins. However, many challenges must be overcome if the application of nanotechnology is to realize the anticipated improved understanding of the pathophysiological basis of disease, bring more sophisticated diagnostic opportunities, and yield improved therapies. The advantages of using nanoparticles as a drug delivery system include: Particle size and surface characteristics of nanoparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration. They control and sustain the release of drugs during their transportation and at the site of localization, altering organ distribution and subsequent clearance of the drug so as to achieve increase in drug therapeutic efficacy and to reduce its side effects. Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. Drug loading is relatively high and drugs can be incorporated into the systems without any chemical reaction. For preserving the drug activity, this is an important factor. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or by the use of magnetic guidance. The system can be used for various routes of administration including oral, nasal, parenteral, intra-ocular etc.

The treatment of brain disorders is particularly challenging because of a variety of formidable barriers to effective and persistent delivery of therapeutic compounds. From several perspectives the brain is a challenging organ for drug delivery. First, the incidence of degenerative diseases in the brain will increase with the aging population. Secondly, the BBB is well-known as the best gatekeeper in the body toward exogenous substances [40]. Generally pharmaceuticals including most small molecules do not cross the BBB. The endothelial barrier is specifically tight at the interface with the brain astrocytes and can in normal conditions only be passed using endogenous BBB transporters resulting in carrier mediated transport, active efflux transport and receptor mediated transport [41]. However the barrier properties may be compromised intentionally or unintentionally by drug treatment allowing passage of nanoparticles. Nanoparticles are able to penetrate the BBB of in vitro and In vivo models disrupting the temporally the barrier and allowing the incorporation the therapeutic agents into the brain [42]. One interesting pathway to reach introduce drugs with nanoparticles into the brain can be with previous phagocytise using immune cells that are able to across the BBB [43-45] Fig. (1). Nanoparticles are able to penetrate the BBB of in vitro and In vivo models; and therefore can be used to develop diagnostic tools as well as nano-enabled delivery systems that can bypass the BBB in order to facilitate conventional and novel neurotherapeutic interventions such as drug therapy, gene therapy, and tissue regeneration. The ideal nanoparticles properties required for the drug brain delivery are: 1. Nontoxic, biodegradable and biocompatible: There is a large variety of the nanoparticles developed so far, however we will focus on nanoparticles investigated from brain delivery. Nanoparticles made of polybutycyanoacryllate (PBCA) have been intensively investigated since 20 years ago showing that when coated with the non-ionic surfactant polysorbate 80 they permitted to deliver drugs to the brain with many limitations in the pharmacokinetic profile and low stability in blood circulation [46]. Today the best alternative nontoxic, biodegradable and biocompatible for the nanoparticles are made of polylactide homopolimers (PLA) and poly(lactide-co-glycolide) heteropolymers (PLGA) [47]. Particle with diameter below 100nm: Nanoparticles size can influence the biodistribution and bioavailability. The nanoparticles range between 10-1000nm, however, nanoparticles with size above 100 nm the clearance rate by the mononuclear phagocyte system increases with the size, while for sizes below 100nm charge is more important [48] Physical stability in blood to avoid the aggregation: The toxicity of several types of nanoparticles was attributed to a disseminated intravascular coagulation and associated events related to the physical surface properties rather than to the chemical toxicity [49]. Prolonger blood circulation time avoiding the mononuclear phagocyte system: Lacking stealth properties, nanoparticles administered intravenously are rapidly cleared from the blood stream by the mononuclear

Nanoparticles can be prepared from a variety of materials such as proteins, polysaccharides and synthetic polymers. The factors that govern the selection of materials for the preparation of nanoparticles include the size of nanoparticles required, inherent properties of the drug e.g., aqueous solubility and stability; surface characteristics such as charge and permeability, degree of biodegradability, biocompatibility and toxicity, desired drug release profile and antigenicity of the final product. Initially, the intravenous administration of nanoparticles did not prove to be successful in targeting the drugs to the brain. Limitations of drug targeting by nanoparticles was described to reach the central nervous system in appreciable quantity was attributed to their uptake by the reticuloendothelial system. This mechanism significantly removes a large portion of nanoparticles from the vascular space, thus limiting their exposure to the cerebrovasculature and resulting in decreased drug concentration in the brain. The problem of rapid uptake of nanoparticles by the reticuloendothelial system was partially solved by coating them with surfactants [39]. Primary surfactants used include polaxamine 908 and polysorbate-80.

2.

3.

4.

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Nanoparticle loaded with drug

Nanoparticle

drug

Fig. (1). Schematic representation of different actions of nanoparticles within neuron (axon, dendrites or cytoplasm).

phagocyte system and mainly accumulated in liver and spleen [50]. Only pegylated nanoparticles have lower mononuclear phagocyte system uptake and prolonged blood circulation in vivo. 5. BBB targeted and brain delivery: Most of the nanoparticles cannot freely diffuse through the BBB and require receptor-mediated transport through brain capillary endothelium and epithelium from choroid plexus. To improve this property has been carried out nanoparticles with pegylated immunoliposomes that access the brain form blood via receptor mediated transcytosis and deliver their content into the brain parenchyma without damaging the BBB. This requires the presence of receptor specific targeting ligands at the tip of the PEG strands, such as monoclonal antibodies able to trigger the activation of receptors (transferring or insulin receptors) [51-53]. Scalable and cost-effective manufacturing process: The potential use of nanotechnology in medicine for clinical applications always needs an evaluation of cost effective during the manufacturing process. Amenable to small molecules, peptides, proteins and nucleic acids: Due to the hydro solubility of these molecules the preparation method is generally based on the water-in-oil-water solvent evaporation technique [54].

However, proteins are highly organized complex structures that have to be preserved to maintain biological activity. To avoid structural and chemical integrity lost during nanoparticle preparation and storage, each nanoparticle formulation of protein is unique and requires specific adaptation and evaluation [55]. 8. Possible modulation of drug release profiles: Nanotechnology may represent a breakthrough to overcome problems associated with cell therapy. Advances in material biocompatibility and production protocols have put this field close to its clinical application. However, issues such as the possibility of tracking drug-containing nanoparticles, monitoring drug viability, and discontinuation of the therapeutic activity when necessary [56].

6.

7.

Actually, peptides are considered the new generation of biologically active tools because they are key regulators in cellular and intercellular physiological responses, which possess enormous potential for the treatment of various central nervous system diseases [57]. In spite of their clinical potential, native peptides have seen limited use due to their poor bioavailability and low stability in physiological conditions. Some strategies used to improve both bioavailability and uptake of peptide drugs for delivery into the brain was suggested by conjugation to a polymer such as nanoparticles can offer tremendous hope in the treatment of brain disorders. At

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the same manner that we commented previously with other drugs, the polymer conjugation with peptides improves pharmacokinetics by increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes. These new strategies will create new opportunities for the future development of neuro-therapeutic drugs. Recently, Chen et al. developed 29-amino-acid peptide derived from rabies virus glycoprotein (RVG29) peptide conjugated itraconazole-loaded albumin nanoparticles (RVG29-ITZNPs). The RVG29 peptide was conjugated to the albumin nanoparticles using biotin-binding streptavidin as cross linker. They demonstrated that RVG29 significantly facilitated the intracellular delivery of nanoparticles and a significant accumulation was observed for RVG29 nanoparticles in brain. They suggested that these nanoparticles can be exploited as a potential therapeutic formulation for the intracranial fungal infection [58]. Also, alternatives routes to drug delivery to the brain are being developed in the laboratories. In the meantime intravenous administration is most popular choice in clinical studies. However, some approaches that have been gaining considerable attention, such as oral route, inhalation or intratraqueal installation, via migration along the olfactory or trigeminal nerve ending after deposition on the olfactory mucosa in the nasal region, convection enhanced diffusion

and intratechal drug delivery systems in addition to conventional model like intravenous administration. Therefore, the administration route of nanoparticles becomes an important criterion of consideration so as to overcome the physiological barriers of the brain and to achieve high drug concentrations therein [59-62] Table 2. UP-TAKE MECHANISMS INTO BRAIN OF NANOPARTICLES

Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. In its neuroprotective role, the BBB functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Transport from the blood to the brain is limited by the BBB. The barrier is formed by brain endothelial cells that line the cerebral microvessels. It is supported by other cell types surrounding the endothelium, such as astrocytes and pericytes [41]. These surrounding cells contribute to the induction of many barrier characteristics of the endothelium, such as tight junctions, that closely join the endothelial cells together. However, the BBB is also a transport barrier. This aspect is formed by specific transport proteins and transcyto-

Table 2. The administration route of nanoparticles becomes an important criterion of consideration so as to overcome the physiological barriers of the brain and to achieve high drug concentrations therein. Table 2 summarize a list of recent patents employing nanoparticles to treat specifically the brain.

Class Nanocapsules

Function Into Brain Drug delivery

Patent Number TW201006495 WO2009135853

Reference [63] [64] [151] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79]

Gold nanoparticle Magnetic nanoparticle Solid lipid nanoparticle Nanoparticle Gold nanoparticle HDL nanoparticle Nanoparticle Nanoemulsion Hydrophilic nanoparticle Dendritic conjugates Gold nanoparticle Chitosan nanoparticle Manganese oxide nanoparticle Magnetic nanoparticle Lipid nanoparticle Lipid nanoparticle

Drug delivery Drug delivery and imaging Drug delivery Drug delivery Drug delivery Imaging Drug delivery Drug delivery Drug delivery Diagnostic Imaging Imaging Diagnostic Imaging Drug delivery Drug delivery

US2011262546 US2011213193 US2011208161 US2011195125 US2011111040 WO2011044545 MX2010012137 CN101884614 CN101701061 WO2009142754 WO2009136763 US2010260686 KR20100078508 KR20070121788 WO2008024753 WO2008018932

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sis mechanisms that mediate the uptake and efflux of molecules. A very important and an unknown fact about the BBB is the metabolic function. The barrier is formed by the expression of metabolizing enzymes such as growth factors, hormones, peptidases, cytochrome P450 enzymes, and monoamine oxidases [63-65]. All of these barrier functions control and regulate both inward and outward transfer of molecules between blood and the brain. There are several routes for the transport of molecules across the barrier. Paracellular transport of hydrophilic molecules is highly restricted by the tight junctions present between brain endothelial cells. Lipid-soluble molecules with molecular weights below 400 Da are able to cross by transcellular lipophilic diffusion, provided that they are not bound to plasma proteins to a high extent, or form a substrate for a transport system at the BBB. For a variety of molecules that are essential for brain function, such as amino acids, glucose, peptides, and proteins, specific endogenous blood brain barrier transporters exist. These are expressed at both the luminal and the basolateral membranes of the endothelium [66]. These transporters are generally responsible for the transport of small molecules with a fixed size and mass smaller than 600 Da. Carrier-mediated transcytosis is used for the delivery of nutrients such as glucose, amino acids, and purine bases to the brain. It is substrate selective and only drugs that closely mimic the endogenous carrier substrates will be taken up [67]. Endocytosis at the BBB is effectuated through adsorption or receptor binding. Receptor-mediated endocytosis is initiated by the binding of a receptor-specific ligand. Following adsorption or binding, the substance is internalized and transported via the early endosome to the lysosome, or transcytosed to the plasma membrane. The only way for larger molecules and particles such as antibodies, lipoproteins, proteins and nanoparticles to be transported into the brain is via receptor or adsorptive-mediated endocytosis [41] Next to these influx systems, many efflux mechanisms exist at the BBB as well. These include P-glycoprotein, MDR-related protein, ABC transporters, and several others. They restrict entry of molecules into the brain by promoting luminal release of compounds and are important in removing harmful substances from the brain, thereby reducing toxic side effects of central nervous system drug metabolites. RECENT ADVANCES IN THE TREATMENT OF AD WITH NANOPARTICLES Pharmaceutical agents that are used to treat AD are usually administered orally, such as donepezil, memantine, rivastigmine, galantamine and tacrine [7]. However, most of the ingested drugs do not reach the brain in a fully way and are, instead, metabolized totally or partially by the liver. This inefficient utilization of drug may require ingestions of higher drug concentrations that can produce toxic effects in the heart, liver or kidney. Also, many therapeutic agents are poorly soluble or insoluble in aqueous solutions. These drugs provide challenges to deliver them orally or parentally, however these compounds can have significant benefits when formulated through other technologies such as nanoparticles

The greatest obstacle in the treatment of AD with these drugs is often not drug potency, but the physical barriers that render the usual circulatory routes of delivery ineffective [80]. The delivery of drugs to brain is limited by the presence of the BBB. This physical barrier is characterized by tight intracellular junctions (zona occludens) with an absence of fenestrations [41]. Thus, the BBB prevents the uptake of all large molecules and more than 98% of pharmaceutical small-molecule drugs [81]. Furthermore, the BBB expresses high levels of drug efflux pumps such as P-glycoprotein, which actively remove chemotherapeutic drugs from the brain [82]. In addition, diffusion in the brain parenchyma is very weak. Finally, brain tissue is highly sensitive, so only limited doses of therapeutic agents can be used. Many strategies have been developed to overcome these obstacles. Among these, drug delivery nanosystems have been produced to protect therapeutic agents and improve their biodistribution and therapeutic index. These systems include mainly polymer or lipid-based carriers such as nanoparticles including nanospheres and nanocapsules, micelles, dendrimers, nanocrystals, and nanogolds. The technology of nanoparticles represents a promising strategy in which the particles could release therapeutic products immobilized and immunoprotected within polymeric and biocompatible devices [83]. To circumvent the BBB, nanoparticles can be administered directly into the brain via a bolus injection. This has the advantage of delivering much higher concentrations of drugloaded nanoparticles to the brain [84-87]. Based on this concept, last year we patented the therapeutic use of microencapsulation of VEGF (vascular endothelial growth factor) over-expression cells [88, 89]. We generated encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, the double mutant amyloid precursor protein/presenilin 1 (APP/Ps1) mice, which showed a disturbed vessel homeostasis, and of adult C57BL/6 mice. Cranial implants of microencapsulated cells secreting VEGF promoted brain vessel formation within the cerebral cortex of adult C57BL/6 mice compared with the non-transfected cell microcapsules-treated group. Two weeks after implantation of encapsulated VEGF secreting cells in adult C57BL/6 mice, vascular density was markedly augmented in the cerebral cortex in comparison with the control group. This increased effect was maintained during all the treatment and was maximal after 3 months. Our findings confirmed previous evidence of a potential therapeutic benefit of VEGF therapy in brain angiogenesis, neuroprotection and cerebromicrovascular exchange of substrates and nutrients [90]. Several studies have reported the successful use of encapsulated cell implants that allow diffusion of therapeutic factors into biological fluids, including CSF [91, 92]. According to these data, may be feasible and attractive to implant genetically modified cells into peripheral compartments. We propose that implantation of VEGF microcapsules may have a therapeutic value in the treatment and prevention of brain diseases One goal of theses findings was to develop the therapeutic methodology without alter the BBB and reduce the damage of the brain increasing the vascularity at cortical levels and reducing the amyloid-beta deposits [93].

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The penetration of a drug into the brain decreases exponentially with the distance from the cerebrospinal fluid surface, so it is necessary to administer high concentrations of drug into the cerebrospinal fluid compartment. The ependymal surface is thus exposed to very high drug concentrations, which can have toxic side effects. The treatments with nanoparticles releasing growth factors are very promising; however there are side effects due to the route of administration. The intracerebroventricular (icv) administration of NGF (nerve growth factor) resulted in axonal sprouting and Schwann cell hyperplasia on the ependymal or arachnoids surface [94]. The icv administration of fibroblast growth factor (FGF)-2 results in periventricular astrogliosis [95]. A promising therapy against AD has been published, consisting in the local and long term administration of CNTF (ciliary neurotrophic factor) using recombinant cells encapsulated with alginate secreting this neurotrophin factor [96, 97]. The major problem with the introduction into brain of nanotechnology is the slower movement of nanoparticles within the brain due to limited diffusion coefficients and backflow of the injection. This is because of the closely packed arrangement of cells in both the gray and white matter microenvironments. Convection enhanced delivery has been used to overcome these problems. Using an external pressure gradient inducing fluid convection in the brain via a surgically implanted catheter, this method allows a greater volume of distribution to be achieved compared with diffusion alone [98]. A combination of nanotechnology with the convection enhanced delivery technique has shown promising results in brain diseases. CeONP can be used to treat or prevent neurodegenerative diseases, including for example AD, PD or HD. In particular, CeONP having an average size of about 2 nm to about 100 nm can be administered in an amount sufficient to block production of hydroxyl or superoxide radicals, block free radical production by amyloid-beta (1-42), neuronal death, [Ca2+] dysfunction in neurons, lipid peroxidation, decrease loss of dopaminergic neurotransmission, or reduce mitochondrial dysfunction in a cell. CeONP can also be effective in treating conditions involving toxic exposures to compounds that induce mitochondrial dysfunction, such as rotenone, cyanide, carbon monoxide, polychlorinated biphenyls and other mitochondrial toxins [99-101]. Another invention relates to nanoparticles containing physiologically active agents. It was patented a new dispersions containing new nanoparticles within nicotine and cotinine are particularly suitable for transdermal mode of administration (DE102007017298). This methodology is mainly published as antismoking and tranquilizer method, however, also showed activity such as neuro-protector in AD animal models [102]. Two different methods it was recently patented using gold nanoparticles. In one of them described an interesting methodology to prepare gold nanoparticles coated with different layers a polyelectrolyte its use as carriers intended to cross BBB and as medicament for treatment of AD, PD, HD and prion diseases (CA20092742915, WO2010052665). The outer layer of human albumin is essential for the passage and protection of the BBB and the layer of polyelectrolyte avoid the aggregation of the nanoparticles [103].

In the second patent, gold nanoparticles are using such as diagnostic method for AD and associated dementias (KR101003124). This method confirms the presence of amyloid beta aggregation due to binding of gold nanoparticles [104]. Other invention relates to the use of metal nanoparticles for the diagnosis of AD. In this patent, nanoparticles coupled to metal ions was take up by the macrophages that are associated with a mechanism of inflammation correlated with AD, and are able to cross the BBB (US2010111876). Then the nanoparticles has to be detected by MRI, the increasing of this nanoparticles is associated with brain inflammation and dementia [104]. Also, antibodies can be associated with nanoparticles and could be useful for treatment and diagnosis of AD. Monoclonal antibodies have been envisioned as useful agents for human therapeutic and diagnostic applications in vivo. Recent results from human clinical trials suggest that this potential is becoming a reality. Attention is now shifting to the development of methods to produce monoclonal antibodies of a quality acceptable for widespread human use, and in sufficient quantity to be a commercially viable product. Microencapsulation technology has been demonstrated to be suited to the large-scale production of both human and murine monoclonal antibodies of high purity and activity, for use in applications in vivo (US20097473423). It was previously commented the possibility of encapsulating antibodies for the treatment of brain diseases. The same technology using anti-VE-cadherin monoclonal antibodies allowed to open a new alternative for the inhibition of angiogenesis and demonstrates the feasibility of using microencapsulated cells as a control-drug delivery system [105, 106]. Also, it the use of human IgM antibodies encapsulated in alginate, it has been recently patented; it has been proved to have a demonstrated activity in the treatment of demyelinating diseases as well as other diseases of the central nervous system that are of viral, bacterial or idiopathic origin, including neural dysfunction caused by spinal cord injury [107]. RECENT ADVANCES IN THE TREATMENT OF PD WITH NANOPARTICLES PD is a progressive disabling neurodegenerative movement disorder without cure. Loss of dopamine causes critical nerve cells in the brain to fire out of control, leaving patients unable to direct or control their movement in a normal manner. Currently available therapies can neither arrest nor reverse the progression of the disease [108]. Several drugs that boost the levels of dopamine or mimic its effects are available for treating PD, but none has surpasses the clinical efficacy of its biological precursor L-DOPA [109]. Nowadays, the goal of treatment is to reduce symptoms and to allow a person to function normally, and with as few side effects, as possible. Current treatment options include medications and surgery. There are many effective medications for Parkinsons symptoms work by influencing dopamine. The major classes include: levodopa, dopamine agonists, catechol-Omethytransferease (COMP) inhibitors, monoamine oxidase (MAO) B inhibitors, anticholinergics and other medications including amantadine. In recent years there has been increasing interest in developing drug delivery systems able to target pharmacologi-

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cally active molecules in close proximity to their site of action. Among these, liposomes, polymeric or lipid nanoparticles seem to be the most effective in providing tools to interact with biological systems at molecular level with a degree of specificity, to provide neuro-protection and neuro-repair. Actually, increasing interest has been addressed toward the introduction of new therapeutic approaches to obtaining continuous dopaminergic stimulation. The goal of this therapeutic strategy is to reduce the occurrence and severity of LDOPA associated motor fluctuations and dyskinesia, and provides good long-term safety and tolerability. This stimulation can be achieved by the administration of oral dopamine agonists with a long half-life, transdermal, and subcutaneous delivery or with nanoparticles of dopamine agonists. To allow higher concentrations of L-DOPA to reach the brain and to reduce peripheral side effects, the therapeutic approach provides the concomitant administration of LDOPA, carbidopa and entacapone that have been developed in tablet form, standard L-DOPA/carbidopa, L-DOPA/benserazide, L-DOPA/entacapone, L-DOPA/tolcapone associations or long-acting controlled release formulations, LDOPA/carbidopa and L-DOPA/benserazide. Alternatively to solid formulations, LD/carbidopa liquid forms have been developed. Furthermore, the authors examine a series of new L-DOPA drugs and non-dopaminergic drugs for PD treatment including nanoparticles and biocompatible microparticles. Similar strategy was recently developed with the formulation of dopamine loaded chitosan nanoparticles. These nanoparticles revealed that were stable allowing to be used such as potential dopamine carrier systems for PD patients [110]. Another recent strategy, and very similar to dopamine loaded chitosan nanoparticles, was developed with apomorphine distributed with solid lipid nanoparticles. Apomorphine is a dopamine receptor agonist for treating PD with the main problem that it has very poor oral bioavailability. This system allows the apomorphine delivery via oral ingestion, showing higher bioavailability and a better distribution in the striatum [111]. These experimental results suggest that solid lipid nanoparticles may offer a promising strategy for apomorphine delivery via oral ingestion. Nanotechnology hold potential to advance medical treatment through construction of materials with enhanced biological effects, at the atomic scale. Recently, by constructing nanopharmaceuticals it was developed and patented cerium oxide nanoparticles with a potent antioxidant activity preserving neuronal function in a preclinical model of PD [99-101]. A very interesting project it is going on by Amanda Haess group based on develop a novel capillary electrophoresis and nanoparticle-based assay for analysis and separation of plasma samples for PD diagnosis, management, and treatment. This system of capillary electrophoresis needs a small sample volume requirement (can be blood, CSF or brain extracts), allow an excellent separation capability. Samples are injected into the system in the presence of nanoparticles which will serve to significantly enhance both detection and separation efficiencies of the targeted biomarkers [112, 113].

Neurotrophic factors are small proteins necessary for neuron survival and maintenance of phenotype. During the last years they are considered as promising therapeutic tools for neurodegenerative diseases. It is well known that the glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF) protects catecholaminergic cells from toxic insults; thus, its potential therapeutic applicability in PD has been intensely investigated. In recent years, there have been major advances in the analysis of GDNF signalling pathways in peripheral neurons and embryonic dopamine mesencephalic cells. However, the actual physiological role of GDNF in maintaining catecholaminergic central neurons during adulthood is only starting to be unravelled, and the mechanisms whereby GDNF protects central brain neurons are poorly known. Compacted DNA nanoparticles represent a promising non-viral technology that is safe and has been shown to be effective in the lung [114] nasal mucosa [115], eye [116] and brain [117]. Single molecules of plasmid DNA can be compacted by polycations to form colloidally stable nanoparticles that have the minimum possible theoretical size based on the partial specific volumes of the constituent components. Based on this nanotechnology, Copernicus Therapeutics Inc and Yureks group are developing a promising project with compacted DNA nanoparticles to deliver plasmid DNA to brain cells and produce transgene expression of GDNF. The recombinant plasmid DNA encodes for GDNF and compacted into nanoparticles are injected safely into the brain, and successfully transfected brain cells to over-express GDNF and provide neurotrophic support for dopamine neurons [117, 118]. Another study using lactoferrin-modified nanoparticles was also used as a potential non-viral gene vector due to lactoferrin is an interesting molecule key such as braintargeting and BBB-crossing ability. This study administered via intravenous lactoferrin-modifies nanoparticles with GDNF encapsulated. The results showed that multiple injections of these nanoparticles obtained higher GDNF expression and this gene expression was maintained for a longer time. Even, multiple dosing intravenous administration of this treatment could significantly improve locomotor activity, reduce dopaminergic neuronal loss, and enhance monoamine neurotransmitter levels on rat model for PD [119] Other example using other methodology is using encapsulation procedures, it is the case of microencapsulation of PC12 cells (dopaminergic cell line) and also embryonic grafts of dopaminergic cells were able to ameliorate behaviours in rat and primates, after the implant of these microcapsules in experimental parkinsonian models [120, 121]. RECENT ADVANCES IN THE TREATMENT OF LBD WITH NANOPARTICLES LBD is a neurodegenerative disorder characterized by the presence of Lewy bodies in the affected neurons. The Lewy bodies are cytoplasmic inclusions containing alpha-synuclein protein aggregates. LBD affects an estimated 1.3 million individuals in the United States. The main problem of LBD is that the symptoms can closely resemble other more commonly known diseases like AD and PD; therefore it is currently widely under diagnosed. LBD is a term for two related

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diagnoses; it refers to both PD dementia and dementia with Lewy bodies. A poorly understood feature of LBD is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension. The earliest symptoms of these two diseases, LBD and PD, differ but reflect the same underlying biological changes in the brain. Over time, people with both diagnoses will develop very similar cognitive, physical, sleep, and behavioural symptoms [122]. Patients with LBD may present a unique set of symptoms and challenges to family caregivers compared with other types of dementia. Prominent difficulties include motor impairment, activities of daily living disability, recurrent behavioural and emotional problems. Cholinesterase inhibitors are considered the standard treatment for cognitive symptoms in LBD. These medications were developed to treat AD. However, some researchers believe that people with LBD may be even more responsive to these types of medications than those with AD. Movement symptoms may be treated with a PD medication called levodopa. However, some people with LBD are extremely sensitive or may react negatively to certain medications used to treat AD or PD. Abnormally accumulated alpha-synuclein is a pathological hallmark of LBD. However, it is not well understood whether and how abnormal accumulation of alpha-synuclein leads to cognitive impairment or dementia in LBD [123]. Furthermore, it is not known whether targeted removal of alpha-synuclein pathology can reverse cognitive decline. Key treatment targets include cognitive and functional impairments, neuropsychiatric symptoms including intense and persistent visual hallucinations, and parkinsonism. Sixmonth, placebo-controlled randomized controlled trials of the cholinesterase inhibitor rivastigmine have indicated modest but significant benefits in cognition, function, global outcome and neuropsychiatric symptoms in LBD. The evidence base for other cholinesterase inhibitors from clinical trials is inconclusive. More recent clinical trials with memantine in PD and LBD patients indicate a benefit with regard to global outcome, with some suggestion of a specific benefit with respect to sleep disturbance [124]. There is no effective therapy for LBD, thus nanotechnology could not developed any effective nano-carrier to treat it. The unique efforts of this field are to degraded or alter the abnormal alpha-synuclein accumulation in the brain. The inhibition of fibril formation is a potential therapeutic strategy for these conditions. There is several experimental therapies using nanoparticles to clear or prevent the synuclein pathology to treat PD but can be used also in LBD pathology. Vasogen Inc. is working with a preparation of phospholipid nanoparticles incorporating phosphatidylglycerol that has been shown to have neuroprotective effects in PD and LBD. This drug increasing the proteosome system prevents the deficits in motor coordination and dopamine observed in a proteasome inhibitor rat model of PD [125]. Other potential therapeutic strategy is investigated with polyamidoamine (PAMAM) dendrimers as inhibitors of fibril formation in vitro. Although is the first step in the development of new therapy wit this dendrimer, the PAMAM dendrimer caused an inhibition of fibrillation of alpha-

synuclein and could be a potential new drug for PD and LBD [126]. RECENT ADVANCES IN THE TREATMENT OF FTD WITH NANOPARTICLES FTD is late-onset neurodegenerative disorders that are associated with mutations in the TARDBP gene. The product of this gene, TDP-43, has also been identified as the main component of the intracellular inclusions typical of most cases of FTD. This dementia is progressive and gradually destroys the ability to behave appropriately, empathize with others, learn, reason, make judgments, communicate and carry out daily activities. In people under age 60, FTD is the most common cause of dementia and affects as many people as AD in the 45-64 age group. FTD is a clinical syndrome associated with shrinking of the frontal and temporal anterior lobes of the brain. Signs and symptoms vary, depending upon the portion of the brain affected. There are several forms of the disease that lead to slightly different behavioural, language and motor symptoms. Due to the symptoms, FTD can be mistaken for AD, PD or a primarily psychiatric disorder like depression, manic-depression, obsessivecompulsive disease or schizophrenia [127]. At cellular level, FTD is marked by cell loss and scarring in the frontal lobes, parts of the temporal lobes and the deeper brain structures that link to them. The tissue loss results from changes in the proteins that normally help cells function. Unlike AD, the brain tissue of people with FTD does not show plaques and rarely shows tangles. Brain tissue from patients with FTD often shows cellular inclusions in neurons named Pick body. These inclusions stain positively for a Tau protein. About 40% of people with FTD have these tau-positive inclusions. A second type of cellular inclusion found in people with FTD is made up of two other proteins called ubiquitin and TDP-43. Ubiquitin is a protein that is involved with clearing waste products from the cell, while TDP-43 is a protein involved with making proteins from the instructions contained in DNA [128]. Unfortunately, there is no way to reverse the damage caused by FTD yet, but many medications and lifestyle changes can help relieve the symptoms. Furthermore, researchers are actively searching for new treatments and running clinical trials to test promising new medications. Recent evidence suggests that TDP-43 is essential for proper development and involved in several fundamental cellular processes, including gene transcription, RNA processing, and the spatial regulation of mRNA translation. Pathogenic TARDBP mutations that impair TDP-43 function could therefore be related to neuronal degeneration in FTD [129]. At the present time there is no known treatment for diseases involving TDP-43 proteinopathies. As TDP-43 pathology is throughout the brain in FTD, recently it was patented a new therapy using adenovirus and gene delivery for widespread TDP-43 expression in the brain and spinal cord (US20110203007). Accordingly, this invention relates to the fields of novel assays for the study of neurodegenerative diseases and in the future could be combined with nanotechnology for the delivery of the gene into brain. More specifically, this invention describes the use of viral delivery of

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TDP-43 to create assays of diseases involving TDP-43 such as FTD [130]. RECENT ADVANCES IN THE TREATMENT OF VD WITH NANOPARTICLES VD is widely considered the second most common type of dementia. It develops when impaired blood flow to parts of the brain deprives cells of food and oxygen. There is also a form in which a series of very small strokes, or infarcts, block small blood vessels. Individually, these strokes do not cause major symptoms, but over time their combined effect becomes noticeable. This type is referred to as vascular cognitive impairment (VCI) or multi-infarct dementia [131]. The molecular perspective on VD is rather limited; the general concept of this type of cognitive impairment has derived from clinical and imaging findings and is correlated, at the cellular level, with neuronal death and the sudden interruption of neuronal networks. The main pathological changes leading to different forms of VD take place in both large (atherosclerosis and thrombosis) and small (lipohyalinosis and fibrosis) cerebral vessels, secondary to common vascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia. The reduction in cerebral blood flow starts early during vascular disease [132] and, therefore, a major vascular event can be preceded by a variable period of chronic hypoxia. As a result, the brain cellular microenvironment might change and adaptive processes may lead to cellular malfunction, rather than cellular death [133]. The diagnosis may be clearest when symptoms appear soon after a single major stroke blocks a large blood vessel and disrupts the blood supply to a significant portion of the brain. This situation is sometimes called post-stroke dementia. Symptoms of VD can vary, depending on the specific brain areas deprived of blood. Impairment may occur in steps, where there is a fairly sudden, noticeable change in function, rather than the slow, steady decline usually seen in AD. VD symptoms include: confusion, trouble paying attention and concentrating, reduced ability to organize thought or actions, difficulty deciding what to de next, problems with memory, restlessness and agitation, etc. But VD can also develop very gradually, just like AD. Studies show that people with dementia symptoms usually have brain changes typical of more than one type. Because VD is closely tied to diseases of the heart and blood vessels, many experts consider it the most potentially treatable form: monitoring of blood pressure, weight, blood sugar and cholesterol should begin early in life. There is not yet a known cure for VD, so prevention is important. The best way to prevent VD is to lower the risk of stroke. This means getting high blood pressure under control, avoiding cigarettes, and controlling cholesterol levels and diabetes. The FDA has not, as yet, approved any medications for the treatment of VD. However, a number of medications used to treat the cognitive symptoms of AD appear to work for VD, too (cholinesterase inhibitors and memantine). At the same manner that other neurodegenerative disease there is no effective therapy for VD, thus nanotechnology could not developed any effective nano-carrier to treat it.

The unique efforts of this field are to detect different markers of hypoxia such as hypoxia inducible factor-1 (HIF-1). HIF1 was used experimentally as a biomarker of hypoxia in the cortex of young and old spontaneously hypertensive rats [134]. Interestingly, the increase in HIF1 was documented only in aged animals, along with an imbalance between microvessels and astrocytes at the level of the neurovascular unit. In hypoxic conditions, HIF-1 is upregulated, translocates into the nucleus, and binds to hypoxia responsive elements of target genes, such as vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT1), lactate dehydrogenase (LDH), erythropoietin (Epo), and nitric oxide synthase (NOS). This molecular pathway can open new potential therapies combining growth factors and nanotechnology. Using this concept our laboratory generated and patented (WO2010089442 and WO2010010223) new encapsulated VEGF-secreting cells and implant them in a transgenic mouse model of AD, which showed a disturbed vessel homeostasis [89, 90]. Cranial implants of microencapsulated cells secreting VEGF promoted brain vessel formation within the cerebral cortex of adult C57BL/6 mice compared with the non-transfected cell microcapsules-treated group. Two weeks after implantation of encapsulated VEGF secreting cells in adult C57BL/6 mice, vascular density was markedly augmented in the cerebral cortex in comparison with the control group. This increased effect was maintained during all the treatment and was maximal after 3 months. Our findings confirmed previous evidence of a potential therapeutic benefit of VEGF therapy in brain angiogenesis, neuroprotection and cerebromicrovascular exchange of substrates and nutrients [93]. Similar invention was also recently patented using nanoparticles composed of chitosan, poly-glutamic acid, and at least one protein drug or bioactive agent characterized with a positive surface charge and their enhanced permeability for paracellular protein drug and bioactive agent delivery. This protein drug can be different angiogenic and neurotrophic growth factors such as VEGF, HIF1, and IGF-I [135]. Other invention provides slow releasing nanoparticles of huperzine A for curing specifically AD and VD [136]. RECENT ADVANCES IN THE TREATMENT OF PRION DISEASES WITH NANOPARTICLES Prion diseases, also known as transmissible spongiform encephalopathies (TSE), are a family of fatal neurodegenerative disorders [137-140]. Prion diseases include Scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) in cattle, Chronic Wasting Disease (CWD) in deer, elk and kuru, Creutzfeldt-Jakob disease (CJD), Fatal Familiar Insomnia (FFI) and Gerstmann-Straussler-Scheinker syndrome (GSS) in humans. Clinically disease is characterised by dementia and motor dysfunction, and neuropathologically by amyloid deposition (in the form of prion protein), spongiform changes in the brain (holes in the tissue with resultant spongy architecture due to vacuole formation in neurons) and neuronal loss. However, the clinical symptoms can vary between and within the different prion syndromes. The progression of prion diseases is rapid, after the initial onset of

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symptoms death normally ensues within 1-3 years [141, 142]. The mature human cellular prion protein denoted PrPc consists of 209 amino acids. Invariably, all of these diseases involve the modification of the endogenous and functional PrPC into a nonfunctional but much more stable form (PrPSc) giving rise to the so-called amyloid plaques in the brain and other nervous tissues [143]. Prion diseases either occur spontaneously without explanation, or are acquired through exposure to prion-infected tissue, or are inherited through mutations of the prion protein gene (PRNP). The protein-only hypothesis is the most widely accepted model that explains the nature and replication of prions and the transmission of the disease. Prions are devoid of nucleic acid and seem to be composed exclusively of the scrapie isoform of the prion protein designated PrPSc. Soluble, protease-sensitive PrPC is converted into PrPSc, which is protease-resistant, through a process whereby a portion of its a-helical and coil structure is refolded into a -sheet structure. Consequently, PrPSc exhibits a high propensity to aggregate. It is thought that PrPSc acts as a template upon which PrPc is refolded into the PrPSc isoform through a process possibly facilitated by another protein or molecular chaperone. It is thought that PrPSc is responsible for the neurodegenerative processes in prion diseases. Detection of its presence for contention in cattle or diagnosis in humans or blood transfusion banks [144] is very difficult even by state of the art immunological methods such as fluorescence immunoassay, RIA, or ELISA [145] or protein misfolding cyclic amplification, which can be. The development of unique detection techniques capable of accurately detecting/diagnosing the presence of prions in the blood or serum of infected but not clinically sick animals to avoid the dissemination of the disease is therefore much needed. Recently it was published a promising method to detect prions in biological fluids before to the appearance of the first symptoms [146]. The major challenge of prion disease diagnosis at the presymptomatic stage is how to sensitively or selectively discriminate and detect the minute quantity of disease associated prion protein isoform in complex biological systems such as serum and brain homogenate. In this contribution, there were published different strategies using different aspects of the nanotechnology with quantum dots [147, 148] and suparamagnetic nanoparticles [149]. Magnetic nanoparticle capture presents an interesting and important utility to decontaminate biological products derived from potentially contaminated sources. Other methods, such as sodium hydroxide, sodium hypochlorite, and phosphotungstic acid treatments, destroy or remove prions but also damage the material of interest. In contrast, magnetic nanoparticles capture PrPSc with specificity [149]. Obviously, the developing of this technique can be applied also to prion detection in biological samples. Calvo et al. employed a novel strategy by using PEGylated polycyanoacrylate nanoparticles as vector for drug delivery in experimental model of prion disease [150]. The work showed that these nanoparticles produced a higher up-

take by the spleen and the brain which are the both target tissue of PrP. To date, there have been no reports showing that any compound can reverse or ameliorate prion disease progression following the onset of neurological symptoms. However, several patents were published using nanoparticles to treat different prion disease: US2011262546, WO2010151085 and WO2010121000. The current therapeutic challenges are to stop the further production of PrPSc molecules, and to remove the PrPSc molecules that accumulated during the pre-symptomatic phase of the disease. Given the extreme chemical and physical resistance of infectious prions to inactivation, accomplishing the latter task without disrupting normal cellular physiology would appear daunting. However, in vitro studies with a number of different nanoparticles suggest that this technology might be able to inactivate or eliminate PrPSc molecules though unique interactions that do not compromise cell viability [151-154]. CURRENT & FUTURE DEVELOPMENTS Neurodegenerative diseases are one of the most serious health problems in the industrialized world. The use of nanotechnology in neurodegenerative medicine and more specifically drug delivery is set to spread rapidly. Nanotechnology has proven to have great potential for providing nanotherapeutics modalities to limit and reverse the neuropathology of neurodegenerative diseases, such as AD and PD, by supporting and promoting functional regeneration of damaged neurons, providing neuroprotection, and facilitating the delivery of neuroactives such as drugs, growth factors, genes and cells across the BBB Table 3. One of the main problems to recover the brain function is that the neurons are relatively difficult targets for genetic manipulation, presenting obstacles for both basic research and therapeutic development. Based on this aspect, biomaterials are playing an increasingly important role in the development of novel, potentially efficacious approaches to brain treatment and repair. Programmable biomaterials enable and augment the targeted delivery of drugs into the brain and allow cell transplants to be effectively delivered and integrate into the brain, to serve as delivery vehicles for therapeutic proteins, and rebuild damaged circuits. Nanoparticles can easily enter brain capillaries before reaching the surface of the brain microvascular endothelial cells, under the condition that the surface of these colloids is modified in a proper way (i.e. by PEG). The prolonged blood circulation of these surface-modified nanoparticles enhances exposure of the BBB, which favours interaction and penetration into brain endothelial cells. Passage of the BBB may also be achieved by masking certain drug characteristics preventing or limiting binding to cellular efflux systems like pglycoprotein or via an LDL receptors-dependent pathway forming a complex with LDL in the blood stream. Other promising routes for reaching the brain, circumventing the BBB, may be via migration along the olfactory or trigeminal nerve endings after deposition on the olfactory mucosa in the nasal region. In order to increase the specific uptake via the inhalation route nanoparticles have been functionalized by conjugation with bioactive ligands-lectins to the surface of PEG-PLA nanoparticles. However, it needs to

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Table 3. Biological approaches of central nervous system drug delivery primarily emanate from the understanding of the physiological and anatomical structures of the BBB transportation. Further the new nanoparticles developed to enter into brain also it is very important develop new available drugs that can be conjugated with the nanoparticles. Many available approaches are developing the pharmaceutical companies such as conjugation of a drug with antibodies or biological methods for targeting exploit ligands in the form of sugar or lectins, which can be directed to specific receptors found on cell surfaces. Here in this table we enumerate the recent patents of new neurotherapeutic where nanoparticles are developing in different neurodegenerative diseases. AD: Alzheimers disease, PD: Parkinsons disease, HD: Huntington's disease, VD: Vascular dementia, LBD: Lewy Body dementia, FTD: Frontotemporal dementia and prion diseases.
Disease AD AD AD AD AD AD and PD AD AD AD AD AD AD, PD, HD and Prion diseases AD, PD, HD and Prion diseases AD and VD AD and VD AD and VD PD PD PD PD PD PD LBD LBD FTD VD Prion diseases Prion diseases Prion diseases Prion diseases Prion diseases Prion diseases Reference or Patent US20056926888 MX2010012137 CN101884614 CN101701061 WO2007002662 US2009092671 WO2009052295 DE102007017298 KR101003124 US2010111876 US20097473423 CA20092742915 WO2010052665 WO2010089442 WO2010010223 [111] [85] [86] [89, 90, 91, 92] [92, 93] [94] [95, 96] WO2009052295 US2009092671 US20110203007 [110] [122, 123] [124] [125] WO2010121000 WO2010151085 US2011262546 Principle active in the nanoparticles CNTF NGF FGF-2 CNTF CeONP CeONP CeONP Nicotine Ab for diagnosis Macrophages VE-Cadherin Albumin Albumin VEGF VEGF Huperzine A Dopamine Apomorphine DNA microparticles GDNF lactoferrin PC12 cells Phosphatidylglicerol PANAM dendrimers TDP43 VEGF, HIF1, IGF-I Quantum dots Suparamagnetic NP PEGylataed NP Clearance of PrPSc Clearance of PrPSc Clearance of PrPSc

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be stated that both passage of the BBB and the olfactory route only account for up to 2% nanoparticles uptake, and its efficacy with regard to drug delivery needs to make considerable increments before use. However, many of these approaches are gaining momentum because nanotechnology allows greater control over material-cell interactions that induce specific developmental processes and cellular responses including differentiation, migration, and outgrowth. The new generation of nanoparticles might control the delivery of drugs both by prolonging drug circulation and by targeting the drug to the site of action in a specific manner. Further experiments are necessary to the better comprehension of the mechanisms which manage these different nanoparticle-mediated transport of the drugs to the brain, these nanoparticles may be helpful in the treatment of brain diseases, because they offer clinical advantages such as decreased drug dose, reduced drug side effects, increased drug viability, non-invasive routes of administration, and improved patient quality of life. Considering the rapidly ageing western countries population and the resulting increase in the incidence of neurodegenerative diseases, there is an urgent need to address an urgent search for new and promising therapies presented by nanoparticles towards neurodegenerative diseases. New treatments for disease progression and more effective symptomatic therapies are urgently required. The challenge involved in the discovery and development of novel drug targets for the treatment of neurodegenerative diseases is a major task for both the academic and pharmaceutical communities. This area represents the most important unmet medical need in the treatment of central nervous system disease. ACKNOWLEDGMENTS We thank Tania Vazquez for editorial assistance. This work was supported by grants from Xunta de Galicia (INCITE2009, 09CSA051905PR), Ministerio de Ciencia e Innovacin (PI11/00842) and Isidro Parga Pondal programme. CONFLICT OF INTEREST None of the authors of this manuscript have any financial interest that has influenced the results or interpretation of this manuscript. REFERENCES
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