Design of Nanostructures for Versatile Therapeutic Applications

By Alexandru Mihai Grumezescu

Design of Nanostructures for Versatile Therapeutic Applications focuses on antimicrobial, antioxidant and nutraceutical applications of nanostructured materials. Many books discuss these subjects, but not from a pharmaceutical point-of-view. This book covers novel approaches related to the modulation of microbial biofilms, antimicrobial therapy and encapsulate polyphenols as antioxidants. Written by an internationally diverse group of academics, this book is an important reference resource for researchers, both in biomaterials science and the pharmaceutical industry.

• Assesses the most recently developed nanostructures that have potential antimicrobial properties, explaining their novel mechanical aspects
• Shows how nanoantibiotics can be used to more effectively treat disease
• Provides a cogent summary of recent developments in nanoantimicrobial discovery, allowing readers to quickly familiarize themselves with the topic

• Language: English
• Publisher: Elsevier Science
• Release date: Feb 3, 2018
• ISBN: 9780128136683

Book preview

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Series Preface: Pharmaceutical Nanotechnology

Alina M. Holban, University of Bucharest, Bucharest, Romania

Due to its immense applicative potential, nanotechnology is considered the leading technology of the 21st century. The science and engineering of nanometer-sized materials is currently employed for the development of numerous scientific, industrial, ecological, and technological fields. Biology, medicine, chemistry, pharmacy, agriculture, food industry, and material science are the main fields which have benefited from the great technological progress developed in nanoscience.

In the pharmaceutical field, nanotechnology has revolutionized traditional drug-design concept and the art of drug delivery. The idea of a highly specific nanoscale drug for the targeted therapy of diseases is now considered a feasible treatment for severe health conditions.

Some scientists believe that the pharmaceutical domain has been reborn by the important contribution of nanotechnology. The field of pharmaceutical nanotechnology has the potential to offer innovative solutions for all diagnosis, therapy, and prophylaxis domains. Application of nanotechnology tools in pharmaceutical research and design is likely to result in moving the industry from a blockbuster drug model to personalized medicine. The current main focus of clinicians is to treat patients individually, not their general diagnosed diseases, which are usually difficult to diagnose or incorrectly diagnosed. There are compelling applications in the pharmaceutical industry where suitable nanotechnology tools can be successfully utilized. By designing and modifying drugs at nanoscale, pharmaceutical nanotechnology could be useful not only for the development of completely new therapeutic solutions, but also to add value to existing products. This possibility opens perspectives of success for pharmaceutical companies in existing markets, but also for new markets.

Scientists have manifested an impressive interest on the field of pharmaceutical nanotechnology research in recent years. However, we face today a true dilemma of data unavailability, due to the multitude of existing information which can be highly inaccurate and contradictory. This is because of the lack of an efficient model for sorting the plethora of nanotechnology tools and information that exists, and strategically correlate those with potential opportunities into different segments of pharmaceutical research and design.

This series is trying to cover the most relevant aspects regarding the great progress of nanotechnology in the pharmaceutical field and to highlight the currently emerging trend of pharmaceutical nanotechnology towards the personalized medicine concept.

The 10 volumes of this series are structured to wisely offer relevant information regarding basic concepts and also to reveal the newest approaches and perspectives in pharmaceutical nanotechnology.

Nanoscale Fabrication, Optimization, Scale-Up and Biological Aspects of Pharmaceutical Nanotechnology, introduces the readers into the amazing field of nanoscale design. Also, this volume facilitate understanding of the biological requirements of nanostructured pharmaceutical formulations for advanced drugs.

In Design and Development of New Nanocarriers, the most recent progress made on the field of nano-delivery is discussed. Modern nanostructured drug carriers employ innovative solutions for the detection and treatment of various diseases in a personalized and efficient manner.

Design of Nanostructures for Theranostics Applications, highlights the impressive impact of nanotechnology in the development of combined diagnosis and therapy concept: theranostics.

Design of Nanostructures for Versatile Therapeutic Applications, offers a dynamic solution for immune modulation, treatment of diseases by natural-based products and infection control, while employing nanostructured solutions to achieve top results.

Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, is a highly investigated and debated field; tissue engineering, is dissected through this volume. Here is shown how nanotechnology has advanced research and applications in the manipulation and engineering of cells and tissues in vitro.

Organic Materials as Smart Nanocarriers for Drug Delivery, deals with the specific world of organic nanomaterials, revealing their wide applications, types, and advantages in drug delivery.

In the volume entitled: Inorganic Frameworks as Smart Nanomedicines, the main focus is to discuss the variety and properties of inorganic nanostructures for therapy and drug delivery in the context of improved personalized medicine.

Lipid Nanocarriers for Drug Targeting, deals with recently developed lipid nanostructures and the advances made in drug targeting.

Drug Targeting and Stimuli-Sensitive Drug Delivery Systems, dissects smart stimuli-responsive nanosystems employed to specifically detect various biochemical conditions and control the release of drugs.

Fullerenes, Graphenes and Nanotubes, reveals major findings made on widely applied drug-design nanosystems, namely fullerens, graphenes and nanotubes. The impact of these nanostructures in pharmaceutical research is highlighted.

All 10 volumes are nicely illustrated and chapters are organized into a logical manner to be accessible to a wide audience. The series is a valuable resource of new and comprehensive scientific proof on the intriguing and emerging field of pharmaceutical nanotechnology, which could be of a great use for scientists, engineers, pharmaceutical representatives, clinicians, and any non-specialist interested user.

Preface

Alexandru M. Grumezescu, University Politehnica of Bucharest, Bucharest, Romania

The aim of this book is to present the recent progress achieved in last years in the field of therapeutic applications from a nanotechnological point of view. The book covers novel approaches related to quorum sensing, antimicrobial therapy, brain targeting, Parkinson’s disease, cardiac repair, skin care, and other hot topics.

Design of Nanostructures for Versatile Therapeutic Applications contains 15 chapters, prepared by outstanding researchers from India, Portugal, South Korea, Portugal, Italy, Greece, Ireland, Brazil, New Zealand, India, United States, and Egypt.

Chapter 1, Nanotechnology and Parkinson’s disease, prepared by Ioannis N. Mavridis et al., reviews the recent progress about potentially useful nanotechnology applications in the diagnosis and management of Parkinson’s disease patients. Nanomaterials have been studied in experimental models of Parkinson’s for the administration of anti-parkinsonian agents, neurotrophic factors, antioxidants, neuroprotective, and antiapoptotic factors. Nanotechnology-enabled naso-brain drug delivery, viral vectors, gene nanocarriers, and exhaled breath analysis with nanoarray are other examples of nanotechnology applications.

Chapter 2, Stem cell and gene-based approaches for cardiac repair, prepared by Ibrahim Elmadbouh et al., gives an up-to-date overview about novel therapeutic interventions, such as administration of recombinant or purified proteins, cell, and gene therapies used to compensate for the loss of cardiomyocytes and to limit the process of left ventricular remodeling. These approaches have been evaluated for both use alone and as adjuncts to bypass grafting in patients who are not candidates for coronary artery surgery. Induced pluripotent cells from adult somatic cells, ex vivo cell-based gene therapy, and endogenous progenitor stem cells mobilization by mobilizing drugs alone or/and as an adjuvant with stem cell therapy into ischemic tissues may represent new directions for cardiac repair. Recently, stem cell exosome-based therapy in clinical setting may represent a novel and viable cardio-regenerative strategy.

Chapter 3, Nanostructured lipid carriers: Revolutionizing skin care and topical therapeutics, prepared by Sheefali Mahant et al., attempts to discuss nanostructured lipid carriers (NLCs) as carrier systems for delivering topical and dermatological actives. The chapter provides a comprehensive account of their composition and preparation techniques, factors affecting the performance of these nanocarriers and the mechanism of their action on skin. Furthermore the review sheds light on the characterization of NLCs and their benefits typical to cutaneous application and skin care.

Chapter 4, Nanotechnology for ocular drug delivery, prepared by Priyanka Agarwal et al., describes the ocular anatomy and introduces details on how different delivery routes target unique therapeutic sites. Barriers to drug delivery by each route are discussed and the use of nanoparticles to circumvent these, through prolonged retention and improved targeting, is highlighted. Finally, current limitations preventing rapid growth of nanotechnology in the ocular domain are elaborated on with an emphasis on both toxicity and commercialization of established and investigative nanomaterials and nanoformulations alike.

Chapter 5, Polymeric nanoparticles and sponges in the control and stagnation of bleeding and wound healing, prepared by Andreza Maria Ribeiro et al., refers to the field of the nanoparticulate medical devices, such as polymeric sponges impregnated with different types of nanoparticles (NPs) loaded with active molecules and their use for promoting hemostasis in tissue and wounds. At first, the most used polymers to control the mechanism of physical coagulation and avoid the blood loss will be discussed. In next topic, an approach about properties, advantages, and limitations of the different polymeric NPs that have been used in combination of medical devices, followed by their use as active molecule carriers for better control of infections and improve wound healing. Finally, a brief discussion about clinical research that has been developed with these materials as bleeding control bandages.

Chapter 6, Nanotechnology approaches to pulmonary drug delivery: Targeted delivery of small molecule and gene-based therapeutics to the lung, prepared by Rachel Gaul et al., give an overview of all aspects of the lungs as a drug delivery site for nanotherapeutics, current challenges, and strategies to design an ideal lung specific-therapeutic. A number of respiratory diseases have a genetic basis and gene therapy approaches for these conditions are also discussed. Nanotechnology approaches to treat various pulmonary diseases are presented and a number of novel therapeutics being investigated in both early stage research and in the clinic particularly gene-based, inhalable therapeutics are described.

Chapter 7, Brain targeting with lipidic nanocarriers, prepared by Sophia Antimisiaris et al., gives an up-to-date overview of lipidic nanocarriers that facilitate drug targeting to the brain. Initially, a brief presentation of the problem to deliver drugs to the brain, due to the blood–brain–barrier (BBB), and the related medical needs is made, followed by a description of the methods currently applied for transport of drugs across the BBB. The structure, advantages, and limitations of the most important lipidic nanocarriers applied for (targeted) delivery of drugs and nucleic acids are then analyzed, and examples from recent reports for each nanocarrier type are mentioned. A brief description of the main diseases targeted is also included. Finally, the current limitations and future perspectives are summarized.

Chapter 8, Nanotechnological approaches for colon-specific drug delivery for modulating the quorum sensing of gut-associated pathogens, prepared by Vijay Kothari et al., begins with an overview of colon microbiology and its resident microbiota, some background information on quorum sensing (QS), and then the description of various strategies for QS modulation, including nanotechnological approaches. In the initial part, the contributors tried to explain the need for QS modulation in the gut, and in the later part how it can be done. Here, the contributors used the term QS in a very broad sense, referring to all sorts of biological communication based on chemical signals, including that taking place between human body and its microbial tenants.

Chapter 9, Psoriasis vulgaris—Pathophysiology of the disease and its classical treatment versus new drug delivery systems, prepared by Fernandes, A.R. et al., discusses the pathophysiology of the disease, the different types of lesions and the available treatments, including nanoparticles with improved therapeutic outcomes.

Chapter 10, Getting under the skin: Cyclodextrin inclusion for the controlled delivery of active substances to the dermis, prepared by Susana S. Braga et al., reviews the applications of cyclodextrins (CDs) in the controlled delivery and stabilization of active ingredients used in cosmetics and other skin formulations. The use of CDs for the molecular encapsulation of active substances brings relevant contributions for the good performance of products, by two different modes of action: allowing a stable and sustained release, or promoting uptake due to the skin penetration enhancing effect of selected CDs. The benefits and challenges of dermocosmetic and dermotherapeutic applications of CDs, from the physicochemical aspects to the formulation and regulatory standpoints, are addressed.

Chapter 11, Preparation of high-valence bifunctional silver nanoparticles for wound-healing applications, prepared by Baskaran Purushothaman et al., addresses bimodal therapeutic silver nanoparticles that have direct wound-healing as well as antibacterial properties.

Chapter 12, Metal nanoparticles as potent antimicrobial nanomachetes with emphasis on nanogold and nanosilver, prepared by Sudarshana Borah et al., focuses on the diverse functions of metallic nanoparticles, with their possible inhibitory mechanisms of action as antimicrobials and a comparative account on the applications of nanogold and nanosilver.

Chapter 13, Modulation of microbial quorum sensing: Nanotechnological approaches, prepared by Vijay Kothari et al., give an overview about the importance of nanotechnology in QS-modulators to the target microbial population(s) in a diseased host, or inside a fermentor. Nanotechnology help in achieving the desired QS-modulatory effects on target populations, using minimum concentrations of such modulatory formulations.

Chapter 14, Lipid-based colloidal carriers for topical application of antiviral drugs, prepared by Carla M. Lopes et al., provides an overview of the current lipid-based colloidal carriers developed for topical application of antiviral drugs, and summarizes the most important challenges and strategies that researchers will find when developing formulations with this purpose.

Chapter 15, Encapsulation of pharmaceutically active dietary polyphenols in cyclodextrin-based nanovehicles: Insights from spectroscopic studies, prepared by Pradeep K. Sengupta et al., presents perspectives highlighting recent progress in research on the inclusion of therapeutically potent flavonoids (which comprise the most important group of dietary polyphenols), in natural and chemically modified cyclodextrin nanovehicles. Recent findings in this area, through explorations via different spectroscopic tools (encompassing UV-visible absorption, fluorescence, and induced circular dichroism), together with supporting molecular modeling studies, are highlighted.

www.grumezescu.com

Chapter 1

Nanotechnology and Parkinson’s disease

Ioannis N. Mavridis¹,², Maria Meliou¹,³, Efstratios-Stylianos Pyrgelis¹,⁴ and Eleni Agapiou¹,⁵,    ¹‘C.N.S. Alliance’ Research Group, Athens, Greece,    ²‘K.A.T.-N.R.C.’ General Hospital of Attica, Athens, Greece,    ³‘Sotiria’ General Hospital of Chest Diseases, Athens, Greece,    ⁴University of Athens School of Medicine, ‘Eginition’ Hospital, Athens, Greece,    ⁵‘Asklepieio Voulas’ General Hospital, Athens, Greece

Abstract

The purpose of this chapter is to explore the role of nanotechnology in Parkinson’s disease. Nanomaterials can be engineered to cross the blood–brain barrier, to target specific cells and molecules and to act as vehicles for drugs, enhancing their therapeutic efficacy and/or bioavailability. Nanotechnology has contributed significantly to the study of the pathogenesis of Parkinson’s disease. Nanoparticles can be used for early imaging of neuronal loss and nanodevices can help in the detection/quantification of amyloid peptides in cerebrospinal fluid. Nanomaterials have been studied in experimental models of Parkinson’s for the administration of antiparkinsonian agents, neurotrophic factors, antioxidants, neuroprotective and antiapoptotic factors. Nanotechnology-enabled naso-brain drug delivery, viral vectors, gene nanocarriers and exhaled breath analysis with nanoarray are other examples of nanotechnology applications. Nanotoxicity, however, is a realistic problem in mice and requires further investigation. In conclusion, nanotechnology has several applications potentially useful in the diagnosis and management of Parkinson’s disease patients.

Keywords

Antiparkinsonian agents; α-synuclein; dopaminergic neurons; nanomaterials; nanomedicine; nanotechnology; nanotoxicity; neurodegeneration; Parkinson’s disease

Chapter Outline

1.1 Introduction 1

1.1.1 Parkinson’s Disease 1

1.1.2 Nanotechnology 3

1.1.3 Nanomedicine 3

1.1.4 Purpose 4

1.2 Genetic and Molecular Mechanisms of Parkinson’s Disease 5

1.2.1 Molecular Mechanisms 5

1.2.2 Genetics 7

1.3 Nanotechnology and Parkinson’s Disease 8

1.3.1 Pathogenesis of Parkinson’s Disease 8

1.3.2 Diagnostic Methods for Parkinson’s Disease 10

1.3.3 Management of Parkinson’s Disease 12

1.4 Nanotoxicity 21

1.5 Conclusions 22

References 24

Further Reading 28

1.1 Introduction

1.1.1 Parkinson’s Disease

Parkinson’s disease is a common, multifactoral, progressive, neurodegenerative disorder characterized by a protein fibrillation process and loss of dopaminergic neurons in the basal ganglia. This is mainly due to an abnormal accumulation of α-synuclein in intraneuronal Lewy bodies in the substantia nigra, which leads to subsequent loss of dopamine in the midbrain region (Busquets et al., 2015; Ganesan et al., 2015; Linazasoro, 2008; Majidinia et al., 2016; Mohanraj et al., 2013). This causes an imbalance of neurotransmitters, such as dopamine and acetylcholine, leading primarily to impairment of voluntary and controlled movements (Ganesan et al., 2015; Majidinia et al., 2016). Although not exclusive, the involvement of the dopaminergic system is the most prominent in Parkinson’s disease (Linazasoro, 2008), which is the second most common neurodegenerative disorder worldwide after Alzheimer’s disease (Majidinia et al., 2016).

Parkinson’s disease is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta projecting to the striatum (Zhao et al., 2014). The striatum, the first relay of the basal ganglia system, is critically involved in motor functions and motivational processes. The dorsal striatum is fundamental to motor control and motor learning, whereas ventral striatum, especially the nucleus accumbens, is essential for the reward system, motivation, and reinforcement by drugs. This system is dysfunctional in Parkinson’s disease. With disease progression, beside dopaminergic degeneration, nondopaminergic nuclei (such as the locus coeruleus, the nucleus basalis of Meynert and the dorsal raphe) are affected (Mavridis, 2015).

The clinical symptoms usually appear late in the course of the disease, after more than 60% of the dopaminergic neurons are lost (Kumar et al., 2010). There is a great variety of clinical manifestations among patients related to the balancing effects of compensatory mechanisms, the effects of additional pathologies, the degree of anatomic damage and the constant change of neurotransmission system, especially when Parkinson’s disease is medically treated (Linazasoro, 2008). These manifestations include motor and nonmotor symptoms, resulting in severe disability (Kumar et al., 2010). The major motor symptoms include tremor, speech and writing changes, decelerated movement and muscle rigidity (Ganesan et al., 2015). Nonmotor manifestations include cognitive, behavioral, and autonomic symptoms. Neuropsychiatric symptoms occur in the majority of patients and should be considered as an integral part of the disease. These include dementia and cognitive impairment, depression, dysthymia, anxiety disorders, psychosis, apathy, sleep disorders, sexual disorders, and treatment-related psychiatric symptoms. Neuropsychiatric symptoms are important determinants of mortality, disease progression, and patients’ and caregivers’ quality of life (Mavridis, 2015).

Management of Parkinson’s patients includes neuroprotective or disease-modifying therapies, symptomatic treatment, and surgical interventions. Neuroprotective approaches are based on attacking pathological mechanisms such as oxidative stress, mitochondrial dysfunction, excitotoxicity, caspase activation, apoptosis, inflammation, and trophin deficiency. Many types of medications are available for the symptomatic treatment of Parkinson’s disease, including anticholinergics, amantadine, L-dopa (L-3,4-dihydroxyphenylalanine or levodopa), monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, and dopamine agonists. Surgical management primarily includes deep brain stimulation (DBS) of targets such as the subthalamic nucleus, the internal segment of the globus pallidus, and thalamic nuclei (Jankovic, 2016).

Parkinson’s disease incidence is higher among patients older than 65 years. The continuing aging of populations results in a continuously increasing presence of neurodegenerative disorders. Current treatments of neurodegenerative disorders, which only delay progression and complications during the course of these diseases, cost nearly $20,000,000,000 in the United States of America; a cost that increases every year (Kumar et al., 2010). The socio-economic effects of this phenomenon, call for more efficient methods of diagnosis and treatment of these disorders (Giordano et al., 2011). The expected increase in lifespan of the global population will further lead to a rise in age-related diseases, including neurodegenerative disorders.

1.1.2 Nanotechnology

Nanotechnology uses engineered and appropriately manipulated materials (nanomaterials) that interact with biological systems at a molecular level. According to the National Nanotechnology Initiative, nanotechnology is defined as the manipulation of matters with at least one dimension sized between 1 and 100 nm (Stern and Johnson, 2008). Molecular nanotechnology is an engineering discipline with the goal to build devices and structures that have every atom in the proper place (Kaehler, 1994). This technology has a broad range of research and applications in many fields, including medicine (Stern and Johnson, 2008). In general, nanotechnology allows for an intervention at a molecular level and any desired cellular signaling pathway can be targeted (Linazasoro, 2008). It provides scientists with the potential to interact with various biological systems by stimulating, responding to, and interacting with molecular target sites in order to induce responses, while theoretically minimizing side effects (Modi et al., 2010).

Today, nanotechnology and nanoscience approaches to particle design and formulation are beginning to expand the market for many drugs and are forming the basis for a highly profitable niche within the industry. Nanoscale vehicles and entities can be used, for example, for site-specific drug delivery and medical imaging after parenteral administration. However, some predicted benefits of nanotechnology may be overestimated (Moghimi et al., 2005).

1.1.3 Nanomedicine

Applications of nanotechnology for treatment, diagnosis, monitoring and control of biological systems have been referred to as nanomedicine by the National Institutes of Health (Moghimi et al., 2005). Accordingly, nanomedicine is the process of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body (Freitas, 2005b). In fewer words, nanomedicine is the applications of nanotechnology to the medical field (Stern and Johnson, 2008).

The early genesis of the concept of nanomedicine sprang from the visionary idea that tiny nanorobots and related machines could be designed, manufactured, and introduced into the human body, to perform cellular repairs at a molecular level. Nanomedicine today has branched out in hundreds of different directions, each of them embodying the key insight that the ability to structure materials and devices at a molecular scale can bring enormous immediate benefits in the research and practice of modern medicine (Freitas, 2005a).

The implementation of nanotechnology for medical purposes includes the production of biomedical devices, nanoelectronic biosensors and drug delivery systems. Nanomedicine is a developing field of research and is expected to offer new insight into the study and treatment of various disorders (Andressen and Wree, 2013; Giordano et al., 2011; Mazza et al., 2013). Several types of nanomaterials, with different features, are currently available for medical use (Re et al., 2012). Nanoparticles used in nanomedicine include solid colloidal matrix-like particles made of polymers or lipids. They are mainly administered intravenously and they have been developed for targeted delivery of therapeutic or imaging agents (Linazasoro, 2008).

In the relatively near future, nanomedicine can address many important medical problems by using nanoscale-structured materials and simple nanodevices that can be manufactured today, including the interaction of nanostructured materials with biological systems (Freitas, 2005b). Research into the rational delivery and targeting of pharmaceutical, therapeutic, and diagnostic agents is at the forefront of projects in nanomedicine. These involve the identification of precise targets (cells and receptors) related to specific clinical conditions and the choice of appropriate nanocarriers to achieve the required response, while minimizing side effects. Mononuclear phagocytes, dendritic cells, endothelial cells, and cancer cells (of the tumor or its neovasculature) are key targets (Moghimi et al., 2005). In the mid-term, biotechnology will make possible even more remarkable advances in molecular medicine and biobotics, including microbiological biorobots or engineered organisms. In the longer term, the earliest molecular machine systems and nanorobots may join the medical armamentarium, finally giving physicians the most potent tools in their effort to conquer human disease and aging (Freitas, 2005b).

1.1.4 Purpose

The purpose of this chapter is to explore the role of nanotechnology in Parkinson’s disease, from both a basic science and a clinical point of view. A wide variety of applications of nanotechnology to Parkinson’s disease will be presented, concerning the understanding of its pathogenesis, newly developed diagnostic means, and of course various new therapeutic options, primarily based on the new horizons for brain drug delivery that nanoparticles have recently opened. Before analyzing these applications, a necessary reminding of some basic genetic and molecular mechanisms of Parkinson’s disease will be provided.

1.2 Genetic and Molecular Mechanisms of Parkinson’s Disease

1.2.1 Molecular Mechanisms

The main cause of Parkinson’s disease is the reduction of dopamine-producing cells. Pathologically this occurs due to abnormal intraneuronal protein deposits, named Lewy bodies, in the substantia nigra (Kumar et al., 2015; Majidinia et al., 2016) and in other distinct brain regions (Öhrfelt et al., 2011). The protein α-synuclein, which is a small self-assembly protein, is the main component of these amyloid-like accumulations (Busquets et al., 2015; Ganesan et al., 2015; Kumar et al., 2015; Majidinia et al., 2016; van Rooijen et al., 2008, 2010). These formations lead to dopamine deficiency in the striatum and in other brain nuclei, as well as to an increased firing rate with abnormal firing pattern in the subthalamic nucleus and the internal segment of the globus pallidus (Ganesan et al., 2015; Linazasoro, 2008; Majidinia et al., 2016). Lewy bodies are initially located in the substantia nigra and then spread throughout several areas of the brain. This dispersion process could be caused by neuron-to-neuron spreading of α-synuclein amyloid species via axonal transport between connected areas (Busquets et al., 2015).

A-synuclein is a cytosolic protein and is primarily found in brain tissue, together with β-synuclein, whereas γ-synuclein proteins are mainly found in peripheral nerves. A-synuclein was firstly implicated in neurodegeneration after isolation from amyloid plaques from the brains of Alzheimer’s disease patients (Öhrfelt et al., 2011). It is present in high concentrations in presynaptic nerve terminals and in glia of the brain, but also in the mitochondria (Kumar et al., 2015). The exact way that this protein is involved in Parkinson’s disease is still under investigation. One hypothesis assumes that aggregation of intermediates or oligomers is more likely to be toxic for healthy cells than monomeric or fibrillar forms of the protein. Oligomers are thought to exert their toxicity through inducing permeability of cellular membranes. Membrane pore formation/disruption by oligomeric α-synuclein is considered a likely mechanism of cytotoxicity in Parkinson’s disease (Fig. 1.1). Oligomeric α-synuclein binds to membranes containing anionic lipids and accumulates into liquid disordered domains. The binding of oligomers to the membrane and disruption of the latter require different lipid properties. However, membrane-bound oligomeric α-synuclein does not always cause bilayer disruption (van Rooijen et al., 2008, 2010).

Figure 1.1 A likely mechanism of α-synuclein-induced cytotoxicity in Parkinson’s disease.

Factors leading to protein misfolding and aggregation, as well as the molecular mechanisms underlying these processes, are poorly understood (Yu and Lyubchenko, 2009). Studies have shown the ability of α-synuclein to aggregate in amyloid conformations and spread via neuron-to-neuron transmission, suggesting a prion-like behavior. The key factors that determine this ability of α-synuclein are the intrinsic toxicity of α-synuclein fibers, the peculiar characteristics of oligomeric species, the intracellular localization of the protein, and its difficulty to be secreted. Fortunately, massive neuronal invasion as a consequence of distal neuronal spreading has not been observed (Busquets et al., 2015). Research data suggest that, compared to highly dynamic monomeric forms, α-synuclein dimers are practically static and can thus play a role as aggregation nuclei for the formation of aggregates. Using atomic force spectroscopy, two different dissociation channels have been detected, suggesting that aggregation process can follow different pathways (Yu and Lyubchenko, 2009). There is also evidence that this self-assembling protein misfolding process produces more toxic products in the early stages, whereas mature fibrils are less pathogenic (Lakshmanan et al., 2013).

It should be noted here that oxidative stress is another toxic factor considered to be largely responsible for the loss of dopaminergic neurons in Parkinson’s disease (Ganesan et al., 2015; Haney et al., 2015), since dopaminergic neurons are vulnerable to H2O2 production (Kumar et al., 2010). The pathogenesis of the disease is associated with lack of natural antioxidants, such as catalase, glutathione, and superoxide dismutase in the midbrain region. It has been demonstrated that cells of the immune system, particularly microglia, release pro-inflammatory cytokines in response to different stress conditions, which leads to neuronal reduction (Haney et al., 2015). Finally, proteosomal and mitochondrial dysfunction have also been proposed as participating in the development of Parkinson’s disease (Re et al., 2012).

1.2.2 Genetics

Genes are of great importance in Parkinson’s disease pathophysiology (Majidinia et al., 2016; Stefanovic et al., 2015b; van Rooijen et al., 2010). Research on the genetics of Parkinson’s and related diseases has revealed new information about their etiologies and molecular mechanisms. The genetics of these disorders has proven to be much more complex than was originally thought. They display heterogeneity, variable penetrance and expressivity, as well as genetic and sporadic phenotypes. The interplay between Mendelian genes, susceptibility genes, and epigenetics is yet unknown (Goldman and Fahn, 2015). Dysregulation of epigenetics, in terms of histone-mediated acetylation/deacetylation imbalance, however, seems to play a role (Chiu et al., 2013).

Genes associated with autosomal dominant Parkinson’s disease include the α-synuclein (SNCA) gene on chromosome 4q22.1, the leucine-rich repeat kinase-2 (LRRK2) gene (Emelyanov et al., 2013; Goldman and Fahn, 2015), the eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene, the dynactin 1 gene, and the vacuolar protein sorting 35 (VPS35) gene. Genes associated with autosomal recessive Parkinson’s disease include parkin gene on chromosome 6q26 (PARK2), the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene on 1p36.12, and protein deglycase DJ-1 (PARK7) gene on chromosome 1p36.23. Other Mendelian genes have been associated with Parkinson-plus syndromes (Goldman and Fahn, 2015).

Mutations in genes responsible for the production of α-synuclein result in the conversion of α-synuclein from soluble monomers to aggregated insoluble forms, as observed in families with Parkinson’s disease (Öhrfelt et al., 2011). Several amino-acid mutations in the human α-synuclein are related to early onset Parkinson’s disease (Majidinia et al., 2016; Stefanovic et al., 2015b; van Rooijen et al., 2010). Some known mutations are A30P, A53T, and E46K, whereas some recently discovered familial mutations are H50Q and G51D (Stefanovic et al., 2015b). Oligomers formed from these mutations, which aggregate into amyloid fibrils, have similar structure but different membrane permeabilization capacity (Stefanovic et al., 2015b). Recently, several studies in different populations have found a strong association between idiopathic Parkinson’s disease and the single-nucleotide polymorphism rs356219, which is located in the three prime untranslated region of the α-synuclein gene (Pan et al., 2012).

Furthermore, homozygosity of the high-temperature requirement A serine protease 2 (HtrA2) p.G399S allele has been associated with the development of Parkinson’s disease signs in middle-aged patients. Remarkably, both homozygosity and heterozygosity of this allele have been associated with essential tremor. This gene leads to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity. Additionally, loss of function of the high-temperature requirement A serine protease 2 leads to Parkinsonian features in motor neuron degeneration (mnd2) mice (Unal Gulsuner et al., 2014).

Although various Parkinson’s disease-related genes are known, the role of noncoding ribonucleic acids (RNAs), micro-RNAs and long noncoding RNAs should also be emphasized. Micro-RNAs regulate, among other things, the expression of Parkinson’s disease-related genes, whereas long noncoding RNAs affect its pathogenesis (Majidinia et al., 2016).

1.3 Nanotechnology and Parkinson’s Disease

1.3.1 Pathogenesis of Parkinson’s Disease

Parkinson’s disease initiates at a molecular level after gene mutation, alone or in combination with environmental factors (Linazasoro, 2008; Stefanovic et al., 2015b). This leads to dysfunction at a cellular level with protein misfolding and aggregation of α-synuclein (Linazasoro, 2008; Yu and Lyubchenko, 2009), which is, as previously explained, the cornerstone of the pathologic process of the disease (Kumar et al., 2015; Stefanovic et al., 2015b; Yu and Lyubchenko, 2009). Nanotechnology has contributed to the investigation of these aggregations. A single-molecule probing technique has been applied to detect and characterize the misfolding and self-assembling of α-synuclein dimers. Atomic force spectroscopy can detect protein misfolding via enhanced interprotein interaction (Yu and Lyubchenko, 2009).

The binding of α-synuclein to natural membranes is thought to be crucial for its pathological function. Nanotechnology has contributed to the investigation of the detailed interaction of α-synuclein with natural membranes, focusing on two membranes: the inner mitochondrial membrane and the neural plasma membrane. The strong interaction between α-synuclein and these low negative-charged membranes leads to the conclusion that function and pathology of α-synuclein could involve synaptic vesicles and mitochondria. Noteworthy studies have shown that the affinity of α-synuclein to the membrane is influenced by factors including membrane charge, cardiolipin content, membrane phase, lipid saturation, and post-translational modification of α-synuclein (Fig. 1.2) (Kumar et al., 2015).

Figure 1.2 Factors affecting the affinity of α-synuclein to the cellular membrane.

Öhrfelt et al. (2011) studied brains from patients with Parkinson’s disease and dementia with Lewy bodies, and compared them to age-matched healthy brains. Using nanoflow liquid chromatography, in combination with other techniques, they were able to isolate different forms of α-synuclein and to associate some forms with neurodegenerative disorders (Öhrfelt et al., 2011). Rabe et al. (2013) studied the mechanism of α-synuclein aggregation at nanomolar concentrations. According to their study, aggregation can be triggered in vitro in very low (lower than normal) concentrations in the presence of hydrophilic glass surfaces or cell membranes, with two distinct growth mechanisms both resulting in the creation of amyloid structures (Rabe et al., 2013). Hauser et al. (2011) studied the self-assembling of designed peptides and noted that a minimum concentration was needed for gelatinization while elevated temperatures accelerated self-assembly (Hauser et al., 2011). Moreover, Lakshmanan et al. (2013) studied the formation of amyloid fibrils focusing on the self-assembling of natural core sequences, compared them to nanodesigned peptides, and noted great similarity in mechanisms that could allow researchers to use designed peptides for the better understanding of amyloidosis (Lakshmanan et al., 2013).

Furthermore, Semerdzhiev et al. (2014) reported in vitro self-assembly of nanometer-sized α-synuclein amyloid fibrils into well-defined micrometer-sized suprafibrillar aggregates with sheet-like or cylindrical morphology, depending on the ionic strength of the solution. The cylindrical suprafibrillar structures are heavily hydrated, suggesting swollen gel-like particles. In contrast to higher order structures formed by other negatively charged biopolymers, multivalent ions are not required for the formation of suprafibrillar aggregates. This formation is induced by both mono- and divalent counter-ions. The self-assembly process is not mediated by protein-specific interactions but rather by the cooperative action of long-range electrostatic repulsion and short-range attraction (Semerdzhiev et al., 2014).

A better understanding of the pathogenesis of Parkinson’s disease at a molecular level will facilitate rational approaches to prevent or limit its progression and to plan more targeted treatment (Yu and Lyubchenko, 2009). Understanding the mechanism driving the self-assembly might give us valuable insight into the pathological formation of fibrillar superstructures, such as Lewy bodies and neurites-distinct signatures of Parkinson’s disease, and could create the possibility to utilize the self-assembly process for the design of new fibril-based smart nanostructured materials (Semerdzhiev et al., 2014). The advances of nanomedicine have created great expectations in the understanding of the pathophysiology of neurodegenerative disorders, such as Parkinson’s disease. Since the basis of this disorder seems to be on a peptide level, it is apparent that nanotechnology could play a major role in the study of its pathogenesis.

1.3.2 Diagnostic Methods for Parkinson’s Disease

1.3.2.1 Neuroimaging

Diagnosis of Parkinson’s disease is primarily clinical, based on medical history and neurological examination. There are no laboratory tests or imaging exams that confirm the diagnosis. In some cases, the relief of symptoms after L-dopa treatment and the progress of illness tend to confirm the diagnosis. Neuroimaging methods, however, are frequently used in the investigation of these patients to rule out other diseases that may cause parkinsonism. Computer tomography and magnetic resonance imaging brain scans are usually normal or with nonspecific findings. Magnetic resonance imaging could also be used in these patients to correlate symptoms with imaging findings, e.g., cognitive impairment with cortical thickness and/or subcortical volumes (Mavridis, 2015; Pereira et al., 2015). Nanotechnology offers the possibility of particle distribution, for diagnostic purposes, in the central nervous system; an otherwise almost impenetrable compartment, due to the blood–brain barrier (Andressen and Wree, 2013; Giordano et al., 2011; Mazza et al., 2013).

Based on the hypothesis that reactive astrocytic gliosis occurs in conjunction with dopaminergic neuronal loss in the brain, but also in the retina, of Parkinson’s disease patients, research data from animal models suggest that molecular retinal imaging could be useful in the early diagnosis of the disease (Kumar et al., 2010). Additionally, aptamer-based nanotechnology could also be useful as another diagnostic tool for Parkinson’s disease in the future (Sriramoju et al., 2015).

New fluorescence methods could reproducibly account α-synuclein oligomers and research is in progress to determine, using combined single-molecule photobleaching and sub-stoichiometric fluorescent labeling, the aggregation number of supramolecular protein assemblies (Zijlstra et al., 2016). Finally, in the direction of diagnosing neurodegenerative disorders earlier in the course of the disease, in vivo imaging of senile plaques is possible with positron emission tomography using amyloid-β-specific ligands (Tisch et al., 2013). In a similar way, nanoparticles could also be used for the early detection and quantification of neuronal loss in Parkinson’s disease.

1.3.2.2 Body fluids tests

Cerebrospinal fluid markers used in the diagnosis of neurodegenerative disorders are total-tau, tau-phosphorylated at threonine 181 and amyloid-β. The study of cerebrospinal fluid, however, still has the limitations of an invasive procedure (i.e., lumbar puncture) to obtain it (Tisch et al., 2013). Although biomarkers of Parkinson’s disease have been suggested, none of these is currently in clinical use (Khatib et al., 2014). Khatib et al. (2014) used a rat model in order to identify volatile organic compounds as early biomarkers for Parkinson’s, based on the hypothesis that, during disease progression, specific volatile organic compounds are generated and are linked to biochemical pathways characterizing the disease. In the blood of dopaminergic-lesioned (injected with 6-hydroxydopamine) rats, 1-octen-3-ol (a cytotoxic compound) and 2-ethylhexanol were found at significantly higher concentrations compared to sham rats. The authors suggested that these results may lead to the development of an early diagnostic test for Parkinson’s disease, based on the profiling of volatile organic compounds in body fluids (Khatib et al., 2014).

The detection of catecholamine molecules could potentially serve as a relevant biomarker for specific states of Parkinson’s disease, or as a monitoring tool for treatment efficacy. Recently developed methods are able to detect catecholamines at relevant concentration levels. These methods use electrochemical sensors, which are highly innovative features introduced by nanotechnology, for the selective detection of catecholamines (Ribeiro et al., 2016).

The identification of volatile organic compounds patterns is the basis of new diagnostic tools, and breath analysis is thus gaining ground as a diagnostic tool in several diseases. More specifically, a nanomaterial-based sensor array from exhaled alveolar breath is adapted for the diagnosis of several diseases such as malignancies, multiple sclerosis, and renal diseases (Tisch et al., 2013). Tisch et al. (2013) presented combinations of nanomaterial sensors for the identification of Alzheimer’s and Parkinson’s disease patients. They studied 57 volunteers (15 Alzheimer’s, 30 Parkinson’s and 12 controls), collected exhaled alveolar breath samples and exposed them to an array of 20 nanomaterial-based sensors. When exposed to volatile organic compounds, sensors underwent a rapid and fully reversible change in electrical resistance. Three of the used sensors proved to be able to distinguish the studied groups. Confirmation by larger scale studies, and studies including nonsymptomatic patients, could hopefully lead to the development of an easy-to-use tool for diagnosing neurodegenerative disorders, even in primary care (Tisch et al., 2013).

Furthermore, diagnosis of different parkinsonian syndromes is associated with high misdiagnosis rates and various confounding factors, particularly in the early stages of the disease (Nakhleh et al., 2015). Nakhleh et al. (2015) aimed to distinguish between idiopathic Parkinson’s disease, other parkinsonian syndromes (nonidiopathic Parkinson’s disease), and healthy subjects, by a breath test that analyzes the exhaled volatile organic compounds using a highly sensitive nanoarray. Based on their results, they suggested that exhaled breath analysis with nanoarray is a promising approach for a noninvasive, inexpensive, and portable technique for differentiation between different parkinsonian states. However, a larger cohort seems mandatory to establish the clinical utility of their method (Nakhleh et al., 2015).

1.3.3 Management of Parkinson’s Disease

1.3.3.1 Nanomaterials and drug delivery

Medications currently available for Parkinson’s disease aim to improve and preserve the functional capacity of patients and relieve them from symptoms for as long as possible. However, they do not cure nor modify the progression of the disease. As a result, there is a great need for innovative and more effective therapy. Extensive research is in progress regarding neuroprotective agents, more effective antiparkinsonian agents, antioxidants, stem cell research, vaccines, and various surgical techniques (Singh et al., 2007). The applications of nanotechnology in clinical neuroscience could reverse or limit disease states, support and promote functional regeneration of damaged neurons, provide neuroprotection and facilitate the delivery of drugs and particles, overcoming the otherwise almost impenetrable blood–brain barrier (Andressen and Wree, 2013; Giordano et al., 2011; Linazasoro, 2008; Mazza et al., 2013; Miklya, 2010; Modi et al., 2009, 2010; Soursou et al., 2015).

The formulation of different drugs on nanoparticles has presented several advantages over conventional treatments (Leyva-Gómez et al., 2015). Conventional drug delivery systems to the brain do not provide adequate cytoarchitecture restoration or connection patterns, due to limitations of the restrictive blood–brain barrier (Modi et al., 2009). Several nanodelivery techniques and nanophytobioactive compounds have been studied to increase the delivery efficiency of compounds to target sites. A great variety of phyto-derived bioactive compounds, namely curcumin, resveratrol, ginsenosides, quercetin, and catechin, have been shown beneficial to the treatment of Parkinson’s disease (Table 1.1). They cannot, however, cross the well-protected blood–brain barrier. Nanotechnology has been used to enhance the permeability, solubility, and stability of these compounds and, as a result, to improve their delivery to the brain. As far as the nanodelivery techniques are concerned, several materials have been utilized, such as solid-lipid nanoparticles, nanostructured lipid carriers, nanoliposomes, and nanoniosomes (Ganesan et al., 2015).

Table 1.1

Nanomedicine has emerged as an exciting tool able to improve the treatment of a variety of intractable or age-related brain disorders. Apart from the ability to cross the blood–brain barrier, the most relevant properties of engineered nanomaterials (Fig. 1.3) include their ability to target specific cells and molecules, and to act as vehicles for drugs. Potentially beneficial properties of nanotherapeutics, derived from their unique characteristics, include improved efficacy, safety, sensitivity, and personalization, compared to conventional medicines (Garbayo et al., 2014). Nanoparticles used in drug delivery to the brain can be accompanied by local release of peptides, proteins, genes, or antisense drugs (Ganesan et al., 2015; Haney et al., 2015; Linazasoro, 2008; Miklya, 2010; Soursou et al., 2015).

Figure 1.3 Summary of the most important properties of engineered nanomaterials for the management of Parkinson’s disease and other neurodegenerative disorders.

Nanoparticle therapeutics is an emerging modality for the treatment of Parkinson’s disease as it offers targeted delivery and enhances the therapeutic efficacy and/or bioavailability of neurotherapeutics (Kulkarni et al., 2015). Surface phenomena are a key aspect in the development of functional nanoparticles for Parkinson’s disease (Leyva-Gómez et al., 2015). Multivalent membrane binding sites on the α-synuclein oligomer result in clustering of vesicles and hemifusion of negatively charged model membranes. Multivalent, biological nanoparticles are reminiscent of inorganic nanoparticles in their interactions with membranes. A-synuclein oligomers induce lipid exchange efficiently, with fewer than 10 oligomers/vesicle required to complete hemifusion (Stefanovic et al., 2015a).

1.3.3.2 Antiparkinsonian agents

Dopamine is the basis of Parkinson’s disease treatment. However, dopamine is hydrophobic and cannot cross the blood–brain barrier. L-Dopa is a dopamine precursor that crosses the blood–brain barrier before being converted to dopamine (Malvindi et al., 2011). Although many antiparkinsonian drugs are used, L-dopa remains the most potent and effective. Unfortunately, after some years of treatment the effect of L-dopa is lost and side effects become more intense, limiting its use. Most of these side effects are related to the short action of the drug, which results in a pulsatile and unstable stimulation of dopamine receptors (Linazasoro, 2008). Nanobased approaches have been described for the delivery and release of dopaminergic agents into the brain. Nanoparticles loaded with dopamine seem to be less cytotoxic and more effective in dopamine release than classic dopaminergic agents (Re et al., 2012). Malvindi et al. (2011) studied in vitro the use of CdSe/CdS quantum rods, combined with galactose and succinyl-dopamine with promising results (Malvindi et al., 2011). Mohanraj et al. (2013) studied the development of poly(butylene succinate)-microspheres for the delivery of L-dopa. The products from the degradation of these nanoparticles are considered nontoxic. Double emulsion solvent evaporation technique was used to combine L-dopa with the poly(butylene succinate)-microspheres. The study showed controlled sustained release of the drug, after an initial burst effect, for a period of 32–159 h (Mohanraj et al., 2013).

Tyrosine hydroxylase is an important enzyme of cells that secrete catecholamines, such as dopamine, and provides a rate-limiting step in catecholamine synthesis. As a result, the activity of tyrosine hydroxylase influences patients who suffer from Parkinson’s disease. Nanotechnology has offered the means to study the effect of noggin protein and type of self-assembling nanofibers in tyrosine hydroxylase overexpression. It was found that tyrosine hydroxylase expression with noggin-poor media showed no sign of tyrosine hydroxylase gene expression, whereas when noggin was added to the media containing laminin nanofiber, a significant tyrosine hydroxylase gene expression was shown. So, tyrosine hydroxylase gene expression depends on the type of nanofibers and accompaniment of nanofiber and noggin is necessary to its expression. In clinical practice, the type of scaffold and laminin accompaniment might be useful for the recovery of Parkinson’s disease (Tavakol et al., 2016).

Pyridoxine is administrated, along with L-dopa, in order to reduce the side effects of antiparkinsonian medications. However, excessive dosage of pyridoxine leads to nervous disorder (Raj et al., 2016). Recently, Raj et al. (2016) developed a sensitive and selective electrochemical method for the determination of pyridoxine in the presence of major interferences, including L-dopa, using electrochemically reduced graphene oxide film-modified glassy carbon electrode. This method could be useful in determining the concentration of pyridoxine in human blood serum and commercial drugs (Raj et al., 2016).

Deprenyl/selegiline, another antiparkinsonian agent, is quite an old drug used to treat Parkinson’s disease. It enhances the activity of catecholaminergic neurons in the brainstem. A novel catecholaminergic activity enhancer substance, namely the (−)-1-(benzofuran-2-yl)-2-propylaminopentane, is 100 times more potent than deprenyl, and also enhances the serotoninergic neurons in the brainstem. Tiny amounts of enhancer substances can be closed in liposomes and marked with a specific signal in order to identify the exact location of the target cells. Through the activation of the latter, the drug can exert its specific enhancer effect (Miklya, 2010).

The vast majority of antiparkinsonian agents are administered per os and, consequently, their bioavailability is affected by various factors of the gastrointestinal tract (gastric pH, rate of stomach emptying, dietary proteins, and constipation). Potential applications of nanotechnology to Parkinson’s disease therapy include alternative routes of drug administration, such as infusion pumps and skin patches. The infusion pumps subcutaneously deliver apomorphine and intraduodenally L-dopa. The pump offers the possibility of constant stimulation of the brain dopamine receptors through a continuous dopamine infusion pump technology. The patches allow transdermal delivery of lisuride and rotigotine. Both pumps and patches aim to avoid the fluctuations in dopamine stimulation and control motor fluctuations and dyskinesia at a satisfying level (Linazasoro, 2008).

Nanomaterials have been used for the delivery of several other agents in neurodegenerative diseases, such as rivastigmine, galantamine, tacrine, and others via an intranasal route (Giordano et al., 2011). Nose to brain delivery of neurotherapeutics has been tried by several researchers to explore the virtues of this route, namely circumvention of blood–brain barrier, avoidance of hepatic metabolism, practicality, safety, ease of administration, and noninvasiveness (Kulkarni et al., 2015). Nanotechnology-enabled naso-brain drug delivery has been supported as an excellent means of delivering neurotherapeutics and as a promising avenue for researchers to develop new formulations for the effective management of Parkinson’s disease (Kulkarni et al., 2015).

Furthermore, the enzyme tissue transglutaminase plays a role in the pathogenesis of various neurodegenerative diseases, including Parkinson’s disease. It has been determined that the primarily intramolecular cross-links, formed at nanomolar tissue transglutaminase concentrations, obstruct the folding of α-synuclein into the β-sheet conformations that are predominant in amyloid species. Fast formation of intramolecular cross-links in α-synuclein would be a good way to prevent formation of pathogenic structures (Segers-Nolten et al., 2008).

1.3.3.3 Antioxidants and neuroprotective factors

Oxidative stress leads to the impairment of neural function through several degenerative reactions, such as nitric oxide toxicity, mitochondrial toxicity, and development of several toxic components (Ganesan et al., 2015). Parkinson’s disease is associated with brain inflammation, microglia activation, and secretory neurotoxic activities, including reactive oxygen species. Brain samples from Parkinson’s disease patients have shown reduced levels of redox enzymes, catalase (one of the most potent natural antioxidants), superoxide dismutase, and other antioxidants (Haney et al., 2015). Oxidative stress is obviously largely involved in the development of Parkinson’s disease (Ganesan et al., 2015; Haney et al., 2015).

In Parkinson’s disease mouse models, systemically administered autologous macrophages can deliver nanoformulated catalase to the substantia nigra pars compacta, providing potent anti-inflammatory effects (Zhao et al., 2014). Exosome-based formation is another example of potential nanotechnology-based drug delivery, and exosome-based catalase formulations efficiently accumulate in neurons and microglial cells in the brain, thus producing a potent neuroprotective effect. Exosomes are comprised of natural lipid bilayers that interact with cellular membranes and serve as naturally nano-sized drug delivery vehicles. Additionally, exosome-based nanocarriers can decrease the drug clearance by the mononuclear phagocyte system (one of the main problems of drug nanoformulations), and increase drug transport to the brain. Therefore, exosomes are exceptionally potent carriers for the neuroprotective enzyme catalase (Haney et al., 2015).

A great variety of bioactive compounds (Table 1.1), such as curcumin, resveratrol (da Rocha Lindner et al., 2015), ginsenosides, quercetin, and catechin have proved beneficial to the treatment of Parkinson’s disease, since they could offer protection against loss of dopaminergic neurons due to oxidative stress. As already mentioned, newly developed nanodelivery techniques could overcome the restrictive blood–brain barrier and help to their successful delivery to the brain (Ganesan et al., 2015; Haney et al., 2015). Nanoparticles proposed for the delivery of neuroprotective agents include the fullerene C60 molecule for the increase of lifespan in mice lacking mitochondrial dismutase, and nanoceria for the protection of cells against oxidative stress (Re et al., 2012).

Resveratrol is a potent natural antioxidant with a wide range of pharmacological activities; its oral bioavailability is very low due to its extensive hepatic and presystemic metabolism (Pangeni et al., 2014). Pangeni et al. (2014) aimed to formulate a kinetically stable nanoemulsion using vitamin E:sefsol (1:1) as the oil phase, Tween 80 as the surfactant, and Transcutol P as the co-surfactant, for the better management of Parkinson’s disease. The prepared formulations were studied for globule size, zeta potential, refractive index, viscosity, surface morphology, and in vitro and ex vivo release. The antioxidant activity, determined by using an α,α-diphenyl-β-picrylhydrazyl assay, showed high scavenging efficiency for the optimized formulation. Pharmacokinetic studies showed higher concentration of the drug in the brain, following intranasal administration of the optimized nanoemulsion. Moreover, histopathological studies showed decreased degenerative changes in the resveratrol nanoemulsion–administered groups (Pangeni et al., 2014).

Furthermore, resveratrol-loaded nanoparticles display significant neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced behavioral and neurochemical changes. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine is another factor that contributes to Parkinson’s disease-related symptoms, acting as a neurotoxin that causes striatal oxidative stress and reduces the expression of tyrosine hydroxylase in the striatum. It induces significant impairment of olfactory discrimination and social recognition memory (da Rocha Lindner et al., 2015).

The antioxidant agent, 1,3-bisbenzylimidazolium, a novel imidazolium compound, seems to reverse the reactive gliosis observed in Parkinson’s disease, based on the hypothesis that upregulation of gliosis is triggered by oxidative agents and could respond to antioxidants. Research data from animal models suggest that antioxidant agents, such as the 1,3-bisbenzylimidazolium, slow down neurodegeneration and could be useful in the treatment of Parkinson’s disease in early stages, as small neuroprotective antioxidant molecules could easily cross the blood–brain barrier (Chan et al., 2013; Kumar et al., 2010). Chan et al. (2013) investigated the 1,3-bisbenzylimidazolium-related neuroprotection in a rat parkinsonian model (induced by 6-hydroxydopamine). 1,3-Bisbenzylimidazolium significantly reduced the 6-hydroxydopamine-induced asymmetrical rotation and preferential usage of contralateral forelimbs, as well as beneficially maintained the dopamine level in striatal tissues, by slowing down its metabolism. In addition, it attenuated the activation of astrocytes and microglia, a result suggesting anti-inflammation is an additional mechanism underlying the 1,3-bisbenzylimidazolium-mediated neuroprotection (Chan et al., 2013).

Finally, Mazza et al. (2013) studied the delivery of dalargin, another cytoprotective factor, through the blood–brain barrier with the use of nanotechnology. Dalargin was delivered in mice either alone or via palmitoyl dalargin nanofibers, both intravenously. Dalargin was rapidly metabolized to D-Aka-Leu-enkephalin in plasma, and could not be detected in any of the tissues, whereas palmitoyl dalargin was detected in the brain for up to 4 h after intravenous infusion. Nanofibers were thus shown to protect the agent from degradation (Mazza et al., 2013).

1.3.3.4 Neurotrophic factors

The in vivo therapeutic potential of neurotrophic factors to modify neuronal dysfunctions is limited by their short half-life (Samal et al., 2015). Samal et al. (2015) aimed a biomaterials-based intervention, which protects these factors and allows a controlled release. Hollow fibrin microspheres were fabricated by charge manipulation using polystyrene templates and were loaded with nerve growth factor (NGF). Fibrin-based hollow spheres showed high loading efficiency (>80%). Neurotrophin encapsulation into the microspheres did not alter its bioactivity and controlled release of NGF was observed in vivo. Fibrin hollow microspheres act as a suitable delivery platform for neurotrophic factors with tunable loading efficiency and maintaining bioactive form after release in vivo (Samal et al., 2015).

Successful brain delivery of neurotrophic factors that promote neuronal survival and reverse the disease progression is crucial, especially in the treatment of neurodegenerative disorders such as Parkinson’s disease (Zhao et al., 2014). Zhao et al. (2014) evaluated genetically modified macrophages for active targeted brain delivery of glial cell line–derived neurotrophic factor (GDNF). To capitalize on the beneficial properties afforded by alternatively activated macrophages, cells transfected with GDNF-encoded plasmid deoxyribonucleic acid (pDNA), were further differentiated toward regenerative M2 phenotype. A systemic administration of GDNF-expressing macrophages significantly reduced neurodegeneration and neuroinflammation in Parkinson’s disease mice. Behavioral studies confirmed neuroprotective effects of the macrophage-based drug delivery system. One of the suggested mechanisms of therapeutic effects is the release of exosomes containing the expressed neurotrophic factor, followed by the efficient GDNF transfer to target neurons. Such formulations can serve as a new technology, based on cell-mediated active delivery of therapeutic proteins that attenuate and reverse progression of Parkinson’s disease, and provide hope for those patients who are already significantly disabled by the disease (Zhao et al., 2014).

1.3.3.5 Antiapoptotic factors

Dysregulation of epigenetics, namely histone-mediated acetylation/deacetylation imbalance, seems to play also a role in Parkinson’s disease. Targeting histone deacetylase in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies used the transgenic model of Parkinson’s disease to characterize the neuroprotection actions of a lead compound known to target histone deacetylase in the brain (Chiu et al., 2013). Chiu et al. (2013) investigated the potential neuroprotective effects of a liposomal-formulated curcumin (Lipocurc)–targeting histone deacetylase inhibitor in the protein deglycase DJ-1 (PARK7) gene knockout rat model of Parkinson’s disease. Their results confirmed the Lipocurc’s antiapoptotic and neurotrophic effects. They suggested that these findings warrant randomized controlled trial of Lipocurc in translating the novel nanotechnology-based, epigenetics-driven, drug discovery platform, toward effective therapeutics in Parkinson’s disease (Chiu et al., 2013).

It should be noted here that it would be a great innovation if neuroprotective strategies could act at a gene level, by interfering with the expression of the abnormal gene product. This would lead to prevention of misfolding and aggregation of misfolded proteins and to interference with the signaling pathways leading to apoptosis (Linazasoro, 2008). Table 1.2 summarizes different types of agents which could be delivered to the central nervous system, via nanotechnology methods, for the management of Parkinson’s disease.

Table 1.2

1.3.3.6 Gene therapy and stem cells

Gene delivery is an area of notable interest, where genetic materials (deoxyribonucleic acid (DNA), RNA and oligonucleotides) could be transferred to inhibit undesirable gene expression, or to promote the synthesis of therapeutic proteins (Linazasoro, 2008). Neurotrophic gene therapy aims to restore pre-existing neural function (Pereira and Aziz, 2006). Gene therapy for neurological diseases is a very promising field of science and the first step for its clinical application is the development of effective and safe gene-transfer vectors (Linazasoro, 2008). Those most commonly used in current research are of viral origin (Corso et al., 2005; Linazasoro, 2008; Pereira and Aziz, 2006; Wang, 2008), since viral vectors are considered to be efficient, practical, and safe (Linazasoro, 2008) in comparison to the constant infusion of recombinant factors (Pereira and Aziz, 2006).

A hybrid baculovirus-adeno-associated viral vector has been proposed for gene therapy of Parkinson’s disease. According to this suggestion, the inverted terminal repeats and Rep gene of adeno-associated viruses are incorporated into the genome of baculovirus, creating a hybrid baculovirus-adeno-associated viral vector to prolong the transient gene expression mediated by the baculoviral vector. Sustained transgene expressions could be achieved in human neuronal and glial cell lines, but not in the correspondent rodent cell lines, by using previously constructed composite neuron-specific and astrocyte-specific promoters in this hybrid viral vector (Wang, 2008).

Gene-transfer systems, based on herpes simplex virus type 1 (HSV-1) and nonviral polyethyleneimine and calcium phosphate nanoparticle methods, have also been studied. The vectors were stereotactically introduced to the substantia nigra. The results showed that the amplicon delivery was markedly increased when packaged with a helper virus and was similar to the expression profile achieved with a full-size replication-defective HSV-1 recombinant (Corso et al., 2005).

Developments have also been made in nonviral gene-transfer technology (Linazasoro, 2008; Corso et al., 2005). An example is a nanocontainer that encapsulates pDNA inside PEGylated immunoliposomes, and transports across the blood–brain barrier after intravenous administration. In the case of Parkinson’s disease, the transferred gene could be that of tyrosine hydroxylase (Linazasoro, 2008).

Neurotensin-polyplex is a gene nanocarrier that has potential nanomedicine-based applications for the treatment of Parkinson’s disease, and cancers of cells expressing neurotensin receptor type 1 (Hernandez et al., 2014). Hernandez et al. (2014) assessed the acute inflammatory response to neurotensin-polyplex carrying a reporter gene in mice. Their results supported the safety of neurotensin-polyplex, demonstrating a better safety profile compared with carrageenan, lipopolysaccharide, and carbon tetrachloride (Hernandez et al., 2014).

Lu et al. (2014) described a well-defined culture system based on xeno-free media, which supported efficient reprogramming of normal or diseased skin fibroblasts from humans of different ages, into human-induced pluripotent stem cells (hiPSCs), with a 15–30-fold increase in efficiency over conventional viral vector-based method. It also supported long-term self-renewal of hiPSCs and direct hiPSCs lineage-specific differentiation. Importantly, they demonstrated that Parkinson’s patient transgene-free induced pluripotent stem cells (iPSCs), derived using the same system, could be directed towards differentiation into dopaminergic neurons under xeno-free culture conditions. Their approach could provide a platform for the generation of patient-specific induced pluripotent stem cells as well as derivatives for clinical and translational applications (Lu et al., 2014).

1.3.3.7 Surgical interventions and brain stimulation

Minimally invasive surgical (and radiosurgical) interventions for treating patients suffering from Parkinson’s disease, and other motor disorders, have been used for decades, a field which belongs to the neurosurgical subspecialty of Stereotactic and Functional Neurosurgery. Besides their obvious contribution to the management of Parkinson’s disease, they have offered a lot, over the years, to the indepth understanding of anatomical structures implicated in the disease. Even though there are still many unanswered questions regarding Parkinson’s disease, newly developed surgical techniques have contributed significantly to the understanding of the theoretical framework of this illness (Pereira and Aziz, 2006).

DBS is an established treatment for Parkinson’s disease and many patients worldwide have benefited from this procedure. Bilateral DBS of either the internal segment of the globus pallidus, or the subthalamic nucleus, offers improvement in parkinsonian tremor, bradykinesia, and rigidity. This surgical treatment provides improvement of Parkinson’s disease motor symptoms and provides relief from motor complications of medical treatment. However, the procedure remains limited to specialized centers and appropriate patient selection is crucial for its effectiveness (Pereira and Aziz, 2006). Implanted electrodes could theoretically constitute a potential platform for simultaneous delivery of drugs, or other molecules, that are able to modulate the activity of basal ganglia nuclei. In this context, the implantation of biosensors in the striatum, and other brain nuclei, has been suggested to monitor the levels of dopamine and other neurotransmitters (Linazasoro, 2008).

Existing noninvasive brain stimulation includes transcranial magnetic stimulation and transcranial direct current cranial stimulation. Magnetoelectric nanoparticles could offer a new tool in noninvasive brain stimulation (Yue et al., 2012). Yue et al. (2012) modeled the effect of magnetoelectric nanoparticle stimulation in a patient with Parkinson’s disease. They computed the matching frequencies and concentrations of nanoparticles that are needed to normalize electric sequences in the thalamic area, the subthalamic nucleus, the globus pallidus, and its medial segment. Through their model, they supported the potential use of magnetoelectric particles for brain stimulation (Yue et al., 2012).

Finally, stereotactic brain implantation procedures have been studied for treating Parkinson’s disease. These include implantation of dopamine containing liposomes in the striatum (Linazasoro, 2008), implantation of viral vectors in the substantia nigra (for gene therapy) and stem cell implantation (to generate well characterized dopamine cells which could rewire the substantia nigra) (Corso et al., 2005; Linazasoro, 2008). Novel hyperselective