Book Volume 2
Page: i-i (i)
Author: Frank Boury and Philippe Menei
Page: II-II (II)
Author: Giovanni Tosi
List of Contributors
Page: III-III (III)
Author: Giovanni Tosi
Nanomedicine and Neurodegenerative Diseases: An Introduction to Pathology and Drug Targets
Page: 1-60 (60)
Author: Tasnuva Sarowar and Andreas M. Grabrucker
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Neurodegenerative diseases are debilitating conditions that result in progressive degeneration and death of neuronal cells. One of the hallmarks of neurodegenerative diseases is the formation of protein aggregates. Progressive accumulation of similar protein aggregates is recognized as a characteristic feature of many neurodegenerative diseases. Particularly in Parkinson’s Disease (PD), aggregated forms of the protein α-synuclein (α-syn); and in Alzheimer's Disease (AD) and cerebral amyloid angiopathy (CAA), aggregated Aβ amyloid fibrils form the basis of parenchymal plaques and of perivascular amyloid deposits, respectively. In Amyotrophic Lateral Sclerosis (ALS), the RNA-binding protein TDP-43 is prone to aggregation. The focal aggregates at early disease stages later on result in the spreading of deposits into other brain areas and many neurodegenerative diseases display a characteristic spreading pattern. Here, we will summarize the anatomy and pathology of the predominant neurodegenerative diseases focusing on AD and PD and review their clinical manifestation to highlight the urge of novel therapeutic strategies. Additionally, given that development of treatments requires suitable animal models, the most commonly used model systems are introduced and their pathology compared to the human situation is mentioned briefly. Finally, possible drug targets in neurodegenerative diseases are discussed.
Nanoparticles Targeting Mitochondria in Neurodegenerative Diseases: Toxicity and Challenge for Nanotherapeutics
Page: 61-100 (40)
Author: Michal Cagalinec
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In the past decades, the prevalence of neurodegenerative diseases (NDDs) has risen dramatically with the increasing age of human population. Neurodegeneration is a long-term and complex process resulting in the degeneration of neurons. So far, no causative therapy exists, urging the development of methods for the early diagnostics and efficient therapy. In this respect, nanoparticles (NPs) are considered a promising tool due to their efficient blood-brain barrier penetrance and specific interactions with the cellular components. They can localize to mitochondria, nucleus, and autophagosomes and also interact with the cytoskeletal structures as tubulin and Tau protein. Therefore, as mitochondria represent important target for NPs, the therapeutic potential of NPs together with their toxicity to mitochondria has become an emerging topic. In this review, we describe the current knowledge in targeting NPs into mitochondria in relation to Alzheimer’s and Parkinson’s disease. Furthermore, we propose a novel idea how to compensate the compromised mitochondrial functioning without the delivery of NPs into the mitochondrial matrix, specifically by the development of NPs targeting either cytoskeleton or the proteins of mitochondrial motility and fusion-fission machinery. As the latter face cytoplasm, this approach does not require targeting NPs into the mitochondrial matrix. At the same time, it could be a significant step to improve the therapy of NDDs, since the movement, fusion, and fission are necessary for mitochondria to exchange their membrane material, mitochondrial DNA, and to remove the damaged mitochondria.
Neuronal Mechanisms for Nanotopography Sensing
Page: 101-114 (14)
Author: Ilaria Tonazzini and Marco Cecchini
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Cell contact interaction with extracellular environment cooperates in coordinating several physio-pathological processes in vivo, and can be exploited to manipulate cell responses in vitro. Thanks to recent developments in micro/nanoengineering techniques, nano/micro-structured surfaces have been introduced capable of controlling neuronal cell adhesion, differentiation, migration, and neurite orientation by interfering with the cell adhesion machinery. In particular, this process is mediated by focal adhesion (FA) establishment and maturation. FAs cross-talk with the actin fibers and act as topographical sensors, by integrating signals from the extracellular environment. Here, we describe the mechanisms of nanotopography sensing in neuronal cells. In particular, experiments addressing the role of FAs, myosinIIdependent cell contractility, and actin dynamics in neuronal contact guidance along directional nanostructured surfaces are reviewed and discussed.
Drug Delivery to the Brain by Liposomal Carrier Systems
Page: 115-127 (13)
Author: Anne Mahringer and Gert Fricker
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Endothelial cells of brain microvessels limit the entry into the brain for xenobiotics and many drugs, which otherwise may be therapeutically active in the central nervous system. The ABC transporters, P-glycoprotein and Breast cancer resistance protein, which are predominantly located in the luminal surface of capillary endothelial cells, are key players for this barrier function. Thus, particular efforts have been made to overcome the blood-brain barrier or to circumvent these efflux pumps. The various options for drug transport into the brain include encapsulation of active compounds into delivery systems, e.g. liposomes, which are able to by-pass the export pumps and to convey their payload across the endothelial barrier. The applied systems target receptors at the luminal surface of the blood-brain barrier by using antibodycoupled immunoliposomes, liposomes conjugated to receptor-targeting vectors such as insulin, transferrin and apolipoproteins or cationized albumin-coupled liposomes.
Neuronopathic LSDs: Quest for Treatments Drives Research in Nanomedicine and Nanotechnology
Page: 128-155 (28)
Author: Cinzia M. Bellettato, David J. Begley, Christina Lampe and Maurizio Scarpa
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Lysosomal storage diseases (LSDs) are due to mutations in genes coding for high molecular weight lysosomal enzymes, which result in a deficiency or complete loss of enzyme activity and the consequent storage of undegraded substrate within lysosomes. Therapeutic approaches capable of modifying the natural history of the disease are available today and many have already entered into clinical practice. Among these, enzyme replacement therapy (ERT) represents an approved key treatment for a number of LSDs. Unfortunately, none of the used therapeutic replacement enzymes have, so far, proved to be effectively able to reach the central nervous system (CNS) in significant amounts and arrest neurodegeneration. Thus, currently, only the peripheral disease can be treated with ERT while storage product continues to accumulate in the CNS, resulting in severe neurodegeneration and premature death in childhood for all neurologically affected patients. In recent years, scientific advances in nanotechnology have led to development of revolutionary approaches potentially capable to provide a solution to the still unmet problem of increasing drug delivery across the Blood Brain Barrier. In particular, the growing interest in the medical applications of nanotechnology has contributed to the advent of a new field of applied science named nanomedicine that offers promising strategies to overcome several of the current impediments and disadvantages of ERT. The combination of existing nanotechnology with already available enzymes can, in fact, significantly improve the enzyme delivery opening a promising new era in the treatment of LSDs. This chapter aims to review the most recent advancement in nanomedicine and nanotechnology presenting novel therapeutic approaches designed to address neuronopathic LSDs.
Targeting Brain Disease in Mucopolysaccharidoses
Page: 156-183 (28)
Author: Marika Salvalaio, Laura Rigon, Francesca D’Avanzo, Elisa Legnini, Valeria Balmaceda Valdez, Alessandra Zanetti and Rosella Tomanin
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Mucopolysaccharidoses (MPSs) are a group of inherited disorders due to the deficit of the lysosomal enzymes involved in the degradation of the mucopolysaccharides, which thus accumulate within different organs, taking to a heavy progressive malfunctioning. The disorders involve most of the organ-systems and in the patients affected by MPS I, II, III and VII, also the neurological compartment may be severely affected. Many therapeutic strategies have been proposed along the years, and, following the identification of the genes underlying each disorder, in the last decade some MPSs have taken advantage on the availability of the recombinant enzymes, systemically administered to the patients. Such treatment, however, has hardly shown any effects on the CNS disease, given the inability of the enzymes to efficiently cross the blood-brain barrier. Therefore, the efforts of the last years have been focused on developing new therapeutic strategies targeting this aspect. This chapter summarizes the most relevant proposed, discussing their advantages, limitations and potential applications. Treatment of the brain disease in neuronopathic MPSs, conjugated with an early diagnosis, would represent a milestone in the improvement of patients’ and families’ life condition.
Functional Validation of Drug Nanoconjugates in vivo
Page: 184-198 (15)
Author: Ibane Abasolo, Yolanda Fernández and Simó Schwartz
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Preclinical development of nanotechnology formulated-drugs shares many features with the development of other pharmaceutical products. However, there are some relevant differences. Nanoparticulated therapeutic systems have challenges related to their production, physicochemical characterization, stability and sterilization, but offer special advantages regarding drug solubilization, bioavailability and biodistribution. A good design of the nanoconjugate, should take into account these pros and cons in the specific setting of the target disease. Moreover, researchers should also bear these in mind when planning in vitro and in vivo proof-of-concept assays. In this chapter we will focus in assays required to test the efficacy of a therapeutic nanoconjugate and how appropriate animal models and imaging technologies help to speed up preclinical development. In addition, we will also describe how basic in vivo pharmacokinetic and biodistribution assays aid researchers to optimize the design of a highly active and non-toxic nanoconjugate.
How does “Protein Corona” Affect the In vivo Efficiency of Polymeric Nanoparticles? State of Art
Page: 199-238 (40)
Author: F. Pederzoli, M. Galliani, F. Forni, M .A. Vandelli, D. Belletti, G. Tosi and B. Ruozi
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Nanomedicine is increasingly considered as one of the most promising ways to overcome the limits of traditional medicine and conventional pharmaceutical formulations. In particular, polymeric nanoparticles (NPs) represent one of the most important tools in the nanomedicine field due to their potential in a wide range of biomedical applications such as imaging, drug targeting and drug delivery. However, their application is strongly hampered by limited knowledge and control of their interactions with complex biological systems. In biological environments, NPs are enshrouded by a layer of biomolecules, predominantly proteins, which tend to associate with NPs, forming a new surface named 'protein corona' (PC). Thus, the resulting nano-structure is a new entity, defined as PC-NP complex, featured by new characteristics, different from the original features of the bare NPs. In this chapter, starting from the definition of PC, we critically discuss the physico-chemical properties of polymeric NPs (e.g., size, shape, composition, surface functional groups, surface charge, hydrophilicity/hydrophobicity) and the environmental biological parameters (blood concentration, plasma gradient, temperature) affecting PC formation and composition. We further discuss how the new “entity” generated by the interactions between NPs and proteins in vivo mediates the ability of all the nanosystems to circulate, biodistribute and selectively release the drugs to the target site. We conclude by highlighting the gaps in the knowledge of the PC in relation to polymeric NPs and by discussing the main issues to be addressed and investigated in order to speed up the translatability of NPs into clinical protocols.
Safety of Nanomedicine: Neuroendocrine Disrupting Potential of Nanoparticles and Neurodegeneration
Page: 239-262 (24)
Author: Eva Rollerova, Alzbeta Bujnakova Mlynarcikova, Jana Tulinska, Jevgenij Kovriznych, Alexander Kiss and Sona Scsukova
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The development of nanomaterials (NMs) for applications in biomedicine inclusive of drug delivery as well as medical imaging is currently undergoing an enormous expansion. NMs may have many different forms and characteristics, depending on their size, chemical composition, manufacturing method, and surface modification. The use of NMs in the field of neurodegenerative diseases diagnosis and treatment implies the ability of NMs to cross the blood-brain barrier (BBB) and enter the central nervous system (CNS) in dependence on their physico-chemical properties, composition, and functionalization. The same properties that make the NMs beneficial for their applications may also affect their interactions with biological systems and have unintended consequences on human health. Several in vivo and in vitro studies have demonstrated that intentional exposure to NMs with potential use for diagnostic and therapeutic purposes might induce neurotoxic effects resulting in neurodegeneration in different CNS regions. Recent evidence has indicated that neuroendocrine disrupting effects by the action of NMs in dopaminergic, serotoninergic, and gonadotropic systems might be relevant to neuropathogenesis and neurodegeneration. In line with developmental origin of adult diseases, it is forewarning the evidence that pre- and post-natal exposure to different risk factors including NMs may lead to phenotypic heterogeneity and susceptibility to neurodegenerative diseases in later stages of the life. In the light of the above mentioned events, relevant test models are required to assess: i) the role of NMs in the development and progression of neurodegenerative disease; ii) the effects of NMs on neurodevelopment upon in utero exposure of foetuses or neonatal exposure of pups; or iii) the neuroendocrine disrupting effects during critical period being crucial for the development of neurodegenerative diseases. Early identification of potential negative features of NMs using interdisciplinary research approaches (biological, toxicological, clinical, engineering) could minimize the risk of newly designed/developed nanomedicines.
Page: 263-269 (7)
Author: Giovanni Tosi
Frontiers in Nanomedicine offers an up-to-date understanding of nanomaterials to readers having clinical or biomolecular research interests. Scientists, both aspiring and experienced, will find, in each volume, a comprehensive overview of current molecular strategies for using nanoscale materials in medicine. Nanomedicine and Neurosciences: Advantages, Limitations and Safety Aspects presents different aspects of nanomedicine applied to neuroscience for the diagnosis of disease and the role of nanoparticles in targeted drug delivery systems for neurodegenerative disorders. Topics covered in this volume cover the physiology of neurodegeneration, targeted therapies for Alzheimer’s disease and Parkinson’s disease, blood brain barrier drug delivery systems, in vivo studies of drug nanoconjugates, nanomedicine safety, and more.