Current Application of Nanoparticles in Neurodegenerative Diseases

Advanced nano medicinal field generates many platforms to improve drug transport across the BBB. It has beneficial effects to improve sensory motor and cognitive functions in stroke as well as in different neurodegenerative diseases like Parkinson’s disease, Huntington’s disease, Alzheimer diseases and also cognitive functions of ones.

Nano formulated drugs

The brain is a critical organ for drug delivery from several viewpoints. Blood Brain Barrier (BBB) serves as the finest gatekeeper in the brain, preventing exogenous drugs from entering into it. Moreover, the probability to develop neurodegenerative diseases increases with aging. Thus, the emergence of nanotechnology has been shown a great potential to deliver drug into the brain [1]. Nano-formulation has been hailed as a paradigm shift in drug delivery mechanisms to prevent neurodegenerative disorders. A drug delivery system is described as a mechanism to introduce a pharmaceutical substance into the body to optimize effectivity and retention time by regulating the rate and location to release into the body [2,3]. When a substance is in the nanometer range, it acquires unique physical and chemical characteristics which are important in drug delivery and have considerable pharmacological effects. Nanoparticle’s chemical composition, relatively benign and ease of surface modification make them suitable carriers to deliver numerous drug loads to the targeted sites [4].

Different types of nanoparticles

Currently different types of nanoparticles with different chemical natures are available for neurodegenerative studies. Among them, organic nanoparticles, inorganic nanoparticles and carbon-based nanoparticles are widely used and attracted the interest in the scientific community for their biomedical applications. Several inorganic nanoparticles, for example gold (AuNPs) and silver (Sio₂ NPs) nanoparticles reached in the CNS. Additionally, inorganic nanoparticles have characterized by long term permeability effect and retention effect making them promising candidates for treatment of neurodegenerative disorder. Silver (AgNPs), Iron Oxide (IO₂NPs), Titanium Dioxide (TiO₂ NPs) nanoparticles are applied for bio imaging in different diagnosis processes [5]. In medical application, they are safe, hydrophilic, biocompatible and highly stable in physiological conditions [6]. Organic nanoparticles are widely used on the basis of selection of specific biocompatible and biodegradable polymers. Among them polylactic, polyglycolic acid, poly lactide-co-glycolic acids are used [7]. where chitosan, alginate, albumin and gelatinate belong natural polymer class [8] and used as drug carriers due to their high drug loading and protection abilities.

Nervous system abnormality is known as a neurological disorder resulting from anatomical and biochemical abnormalities of the nerves in the brain and spinal cord. Once exposed, the nervous system has a limited ability to heal itself. Aging speeds up the process of neurodegeneration, which is the phenomenon of structural and functional loss of neurons. The neurons die by apoptotic, autophagy and necrotic pathways, depending on the location and extent of damage [9]. In the course of neurological disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), etc., the neurological system reorients the structure of neuronal circuits in order to maintain neuronal plasticity. Varying degrees of neuronal loss from distinct parts of the Central Nervous System (CNS) characterizes the major neurodegenerative disease. Inflammation is one of the most critical elements that actively causes neuronal damage [10]. Aging is a key factor behind neurodegeneration as neurons fail to respond against reduced glucose utilization and reduced O₂ uptake in aging. The progression of neurodegenerative disorders shares common mechanisms like oxidative stress, mitochondrial dysfunction and cerebral glucose hypo metabolism, gliosis and protein aggregation [11].

Mechanism of actions of nano formulated drugs

BBB restrict the entry of exogenous substances. Nowadays, nanotechnology approaches are used to carry the drugs into the brain as an innovative targeting approach of “differential protein adsorption”[12]. Smaller NPs (less than 100nm), may enter all cells and tissues including the brain, by crossing the BBB [13]. Macrophages are unable to scavenge nanoparticles, NP remains in the blood circulation for a longer period of time and released sustainably. As a result, bioavailability of NPs is likely to be extended will be able to reach target sites for extravasation more easily [14]. Nano formulated drugs with a significant positive or negative potential remain stable in suspension because the surface charge prevents particle aggregation [3]. The beneficial effect of nanoparticles in comparison to others are many which includes the inner core’s high drug loading capacity and the ability to modulate in response to diverse stimuli such as pH and temperature. It is chemically more stable and biocompatible than others, particles smaller than 50nm are ideal for intravenous delivery and circulate in the blood for longer period of time and experience reduced hepatic filtration because of its higher potential. Hence the smaller size of NP is extraordinarily accessed to target areas in the brain by overcoming the BBB [15]. Nanocapsules are widely recognized as effective drug delivery vesicle due to their nontoxic, biodegradability, non-immunogenic and ability to provide sustained drug releasing in the biological system [16]. The stability of the nanoparticle in the bio-environment offers the possibility of using these vesicles as drug carriers [17]. Polymeric nanoparticle made of Poly Lacticco- Glycolic Acid (PLGA) are accepted as drug carriers effectively because of long shelf life, high carrier capacity, and feasibility of various routes of administration including oral route. CNS targeted polymeric nanoparticle penetrate therapeutic agents more easily and risk is reduced in comparison to other therapies [18]. By using PLGA nanoparticulated drug delivery vehicles it delivers functional proteins to the targeted tissue and release the drug/protein at a controlled rate [19]. PLGA nanoparticle is one of the most successfully developed compatible and degradable biopolymer.

Disease specific application

Specific nanoparticles bind to certain proteins for easy transportation to the site of action. For example, the adsorption of Apo lipoproteins is important for the transportation of drugs across the BBB into the brain [20]. It has been shown that an enhanced binding of ApoE and ApoB-100 to PEGylated NPs compared to the non-PEGylated NPs. The attachment of apolipoproteins to a particle surface directly would aid in drug delivery to brain tissue. Indeed, it has been shown that covalent attachment of ApoE3, ApoA-1, or ApoB-100 to albumin NPs significantly transports a bound drug, loperamide across the BBB as opposed to loperamide alone or free NPs with no lipoprotein attachment [20]. Nanovesiculated drugs can specifically target a damaged CNS by overcoming unwanted side effects of the compounds and tissue barriers in the brain in neurodegenerative disorders. Hence, nanoformulations are used for diagnosing and treating AD [21]. Chelating agents because of its binding properties are used for potential AD therapies. However, BBB limits delivery of many traditional chelators which are neurotoxic and thus prevent its therapeutic uses [22]. Thus, nanocarriers with reduced cytotoxicity are allowed for specific delivery to the CNS with cargo of therapeutic chelating agents to treat AD. Dopamine receptor agonist or selective inhibitor of monoamine oxidase is used for treatment of PD. Other drugs such as amantadine or anticholinergic medicine can suppress tremors [23]. Nanomedicine is focussed for PD which is a balance between halting the disease process and improving the delivery of drugs [24]. In PD cell delivery of NP catalase is a new technique by decreasing microglia activated ROS production in the brain regions. NPs were able to cross the BBB by increasing delivery of catalase and remove microglial peroxides when compared with free catalase [25]. Nanomedicine research on ALS has been considered to focus on replenishing function of SOD1 to motor neurons. Hence, PLGA NPs containing SOD1 are used for deliver SOD1 to motor neurons and provide protection against hydrogen peroxide induced oxidative stress in vitro [26]. Mesoporous silica NPs loaded with hydralazine and coated with PEG were able to damage to both cell membrane and mitochondria, by exposure to lethal amount of acrolein in vitro. ANP consisting of a water-soluble fullerene derivative which is functionalized with a selective receptor antagonist (e.g. NMDA) has several advantages for treatment of multiple scleroses [26]. Cerium oxide NPs are also potent scavengers of ROS and provide neuroprotection [27]. Moreover, NP tagged with functionalized receptors can be used as imaging/diagnostics tool for detecting neurodegenerative diseases. SOD encapsulated in PLGA NPs positively affects the rat focal cerebral ischemia reperfusion injury model of human disease [18]. When SOD NPs are administered through the carotid artery during reperfusion, BBB integrity is maintained, edema is prevented, the level of ROS is reduced and neurons are also protected from apoptosis.

The release pattern and kinetics are the most important factors in determining absorption, distribution, metabolism and excretion of encapsulated drugs. Drug delivery in the target zone, requires controlled and sustained release of the molecules of interest. The in vitro release assay is the most common procedure to determine the release kinetics [28]. Nanoformulated drugs, that exhibit sustained release of drugs under in vitro conditions are found to be released rapidly under in vivo conditions. In vivo experimental data suggests that free unencapsulated curcumin released from nanoformulations is rapidly metabolized and excreted in comparison to the encapsulated curcumin because of the metabolic instability of free curcumin [29]. Another example of drug release is resveratrol-loaded nanoparticles. Both curcumin and resveratrol are natural productbased compounds that demonstrate high antioxidant capacity, cardiovascular protective effects, neuroprotective activity (studied in metabolic disorders and neurodegenerative diseases like AD, PD and HD) [30]. In the analysis of the IC50 values, resveratrol loaded PLA-PEG nanoparticles were obtained with time probably due to prolonged drug release characteristic promoted by nanoparticles [31], but this profile was not observed in PLA nanoparticles. Enhancement of water permeation and drug diffusion through the polymer matrix because of the hydrophilicity of the PEG can explain the observed differences. The hydrophilicity of the nanoparticle would also increase by the presence of amphiphilic nature of PEG in the polymeric matrix [32]. These characteristics could contribute to an increase in the drug release profile.

Over the last few years, development of nanomedicine tools has greatly improved the knowledge about CNS pathobiology, thus improved managements for neurodegenerative disorders. The obvious advantage for nanotechnology lies in its small size that can greatly access target cells or tissues. Potential applications for nanomedicine are distributed in different sections of therapeutics, including detection of specified molecules, imaging and localized diagnostics, drug delivery, tissue repairing etc. Moreover, with nano-scale size, the strategies for management of disease alter in an unexpected way; for example, in nano-medicine bioactive compounds might face the ‘quantum effect’, altering the properties of the compound viz. reactivity, electrical conductivity, color and strength. With the world’s population reaching seven billion, the rapid rise of nanotechnology can be regarded as a forerunner of future technology. Chemotherapeutic, anti-inflammatory and neuroprotective agents may prove to be the most potent if they can be effectively targeted to the sites of interest. In recent years, this cutting-edge technology of miniscule format, comprised of tiny nanoparticles, has made a significant impact on every area of our everyday lives, with or without our awareness. Finally, multipurpose nanoparticles with imaging and drug/antioxidant delivery capabilities will provide a significant potential for research and therapy. With the development of various nanoformulations, bioactive compounds/drugs can easily reach the sites of action by overcoming all obstacles, thus leading to effective treatment. The application of nanotechnology in drug designing and therapeutics has the potential to cure a variety of stress-related ailments, including neurodegenerative disorders. As a result, nanomedicines have the potential to significantly boost life expectancy and quality of life in the coming years.

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