PROGRESS IN BRAIN RESEARCH
VOLUME 180
NANONEUROSCIENCE AND NANONEUROPHARMACOLOGY EDITED BY HARI SHANKER SHARMA Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden
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List of Contributors R.J. Andrews, Smart Systems and Nanotechnology, NASA Ames Research Center, Moffett Field, CA, USA M. Aschner, Department of Pediatrics, Pharmacology and The Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN, USA A. Barras, Laboratory of Chemistry and MicroNanotechnology for Therapy, UMR 8161 CNRSUniversité de Lille 2-Université de Lille 1-Institut Pasteur de Lille, Lille Cedex, France D. Betbeder, Laboratory of Physiology, University of Lille, Faculté de Médecine, Lille, France L. Bondioli, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy A.M. Brioschi, Department of Neurology and Laboratory of Clinical Neurobiology, Ospedale S. Giuseppe, Istituto Auxologico Italiano, IRCCS, Verbania, Italy S. Calderoni, Department of Neurology and Laboratory of Clinical Neurobiology, Ospedale S. Giuseppe, Istituto Auxologico Italiano, IRCCS, Verbania, Italy J. Chang, Laboratory of Physiology, University of Lille, Faculté de Médecine, Lille, France and School of Materials Science and Engineering, Tianjin University, Tianjin, China and Laboratory of Blood-Brain Barrier, University of Artois, Faculté des Sciences Jean Perrin, Lens, France R.P. Choudhury, Department of Cardiovascular Medicine, John Radcliffe Hospital, Headington, Oxford, UK L. Costantino, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy C.J. Destache, Department of Pharmacy Practice, Creighton University School of Pharmacy & Health Professions, Omaha, NE, USA N. Dupont, Laboratory of Chemistry and MicroNanotechnology for Therapy, UMR 8161 CNRSUniversité de Lille 2-Université de Lille 1-Institut Pasteur de Lille, Lille Cedex, France W. Feng, School of Materials Science and Engineering, Tianjin University, Tianjin, China F. Forni, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy M.R. Gasco, Nanovector s.r.l, Torino, Italy Y. Jallouli, Laboratory of Blood-Brain Barrier, University of Artois, Faculté des Sciences Jean Perrin, Lens, France J.V. Lafuente, Lab Neurociencias Clínicas y Experimentales (LaNCE), Dpt. de Neurociencias, Universidad del País Vasco – EuskalHerriko Unibertsitatea, Bilbao, España W. Lee, Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL, USA G. Liu, Department of Radiology, University of Utah, Salt Lake City, UT, USA A. Mauro, Department of Neurology and Laboratory of Clinical Neurobiology, Ospedale S. Giuseppe, Istituto Auxologico Italiano, IRCCS, Verbania, Italy and Departement of Neurosciences, University of Torino, Torino, Italy M.A. McAteer, Department of Cardiovascular Medicine, John Radcliffe Hospital, Headington, Oxford, UK v
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P. Men, Department of Radiology, University of Utah, Salt Lake City, UT, USA D.F. Muresanu, Department of Neurology, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania V. Parpura, Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy & Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, Birmingham, AL, USA R. Patnaik, Department of Biomaterials, School of Biomedical Engineering, Institute of Technology, Banaras Hindu University, Varanasi, India G. Perry, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA and Department of Pathology, Case Western Reserve University, Cleveland, OH, USA L. Priano, Department of Neurosciences, University of Turin, Torino, Italy and IRCCS — Istituto Auxologico Italiano, Ospedale S. Giuseppe — Piancavallo, Verbania, Italy B. Ruozi, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy A. Sharma, Laboratory of Cerebrovascular and Pain Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden H.S. Sharma, Laboratory of Cerebrovascular and Pain Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden G.A. Silva, Departments of Bioengineering and Ophthalmology and Neurosciences Program, University of California, San Diego, CA, USA M.A. Smith, Department of Pathology, Case Western Reserve University, Cleveland, OH, USA G. Tosi, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy M.A. Vandelli, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Modena, Italy X.-B. Yuan, School of Materials Science and Engineering, Tianjin University, Tianjin, China G.P. Zara, Department of Anatomy Pharmacology and Forensic Medicine, University of Turin, Torino, Italy
Preface
Recent advancements in our knowledge about Nanoscale materials and their possible effects on the biological system have resulted in an increased awareness about their modulatory role on the human health system (Sharma, 2009a, 2009b; Sharma & Sharma, 2009). However, the effects of these nanoscale materials comprising “microfine particles” normally present in the environment, or “engineered materials from metals” emanating from some industrial sources at certain work places on our central nervous system (CNS) are still not well known (Sharma, 2007). On the other hand, some attempts have been made to use nanodrug delivery to achieve better therapeutic value in clinical situations (Hekmatara, Gelperina, Vogel, Yang, & Kreuter, 2009). In addition, nanoparticles are also used now for neurodiagnostic purposes (Pathak et al., 2009). Based on these studies from the past 3–4 years led to the development of a new discipline, “Nanoneuroscience,” that deals with the effects of nanoparticles on the CNS related to their both beneficial and harmful effects. This book is the first to be solely directed to understand the new developments in the field of Nanoneuroscience and Nanoneuropharmacology that is currently needed by researchers and clinicians alike to follow the rapid growth of this newly emerging field. Research on nanoparticles has attracted the attention of scientists in the past 5 years to find out whether these nanomaterials could affect our vital organs, for example, lung, liver, kidney, and heart adversely when they enter into our body fluid environments possibly through inhalation (Oberdörster, Elder, & Rinderknecht, 2009). However, effects of these nanoparticles on the CNS toxicity in vivo are still not examined in detail (Sharma, 2007; Sharma & Sharma, 2007). Using in vitro models few studies demonstrated neurotoxicity of nanoparticles to neurons and glial cells (Andrews, 2009). This indicates a possible adverse effect on our brain function following exposure to these microfine particles. However, it is still unclear whether human population living in areas that are heavily polluted with carbon nanoparticles due to motor vehicle exhausts, or with silica dust in desert environment are more vulnerable to CNS injuries or combat stress resulting in an exacerbation of their cognitive, sensory–motor disturbances, or brain pathology as compared to normal populations (Andrews, 2009; Campbell, Araujo, Li, Sioutas, & Kleinman, 2009; Sharma, Ali, Hussain, Schlager, & Sharma, 2009; Sharma, Patnaik, Sharma, Sjöquist, & Lafuente, 2009; Sharma & Sharma, 2009; Sharma, Ali, Tian, Hussain, et al., 2009). In addition, whether the neuroprotective effects of drugs are also evident with CNS injuries occurring in nanoparticles inoculated subjects is still unclear (Sharma, Ali, Tian, Hussain, et al., 2009). Thus, the need of the hour is to find out whether our military personnel working in desert environments, where they are exposed to silica dust, are more vulnerable to CNS injuries or heat stress during their combat or peacekeeping operations (Sharma & Sharma, 2007; Sharma, Ali, Hussain, et al., 2009; Sharma, Ali, Tian, Hussain, et al., 2009). In such situations, pharmacological use of nanoparticles, to enhance drug delivery to the brain, could be a great opportunity to enhance the neurotherapeutic capabilities of the known neuroprotective agents (Sharma, Ali, Tian, Patnaik, et al., 2009; Sharma et al., 2007). Based on these investigations, it appears that use of nanodrug delivery could be useful in attaining superior neuroprotection in CNS injuries (Sharma, 2007; Sharma & Sharma, 2007; Sharma et al., 2007). However, it is still uncertain whether nanoparticles used to enhance drug delivery as such may have some neurotoxic effects. Recent developments in this field show that nanoparticles derived from metals can induce profound neurotoxicity probably by inducing breakdown of the blood–brain barrier (Sharma, Ali, Hussain, et al., 2009; Sharma, Patnaik, et al., 2009; Sharma & Sharma, 2007). Furthermore, nanoparticles are also able to vii
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enhance the perception and symptoms of heat stress and lead to exacerbation of brain pathology and cognitive dysfunctions in laboratory conditions (Sharma, Ali, Tian, Hussain, et al., 2009; Sharma & Sharma, 2007). Under such circumstances, normal drugs that are able to induce neuroprotection in normal animals failed to protect brain pathology in nanoparticles-treated animals (Sharma, Ali, Tian, Hussain, et al., 2009). This indicates that nanoparticles exposure alters the physiological response of the organisms following CNS injury or stress and results in aggravation of cellular and molecular reactions within the CNS. Thus, new investigations are needed to further expand our knowledge in the field of Nanoneurosciences and Nanoneuropharmacology. This volume is the first to summarize recent developments in this newly emerging discipline of Nanoneuroscience by leading experts across the world. The volume represents carefully selected and refereed collections of papers by top nanoneuroscientists engaged in this cutting edge research who present their newly available data in the field of Nanoneuroscience and Nanoneuropharmacology. All the chapters included in this maiden volume by leading experts provide “state-of-the-art” knowledge of Nanoneuroscience either dealing with nanoneurotoxicity, nanoneuropharmacology, and/or nanoneurodiagnostic aspect. This book will thus further expand our understanding and can serve as a reference book in the rapidly expanding field of Neurotherapeutics and related disciplines, for example, neuropharmacology, neuropsychiatry, neurotraumatology, neuropathology, neurorehabilitation, neurodiagnostics, neurophysiology, and neurobiology. I strongly hope that this novel volume in this emerging area of Nanoneuroscience will help in an increased understanding on the roles of nanoparticles in neuroscience with regard to their neurotoxicity or neuroprotective capabilities. The volume is indispensable to clinicians and basic researchers alike to find new avenues of Nanoneuroscience research to reduce nanoneurotoxicity and/or to enhance nanodrug delivery to achieve better human health-care effectively in the near future. Hari Shanker Sharma (Uppsala)
References Andrews, R. J. (2009). Nanotechnology and neurosurgery. Journal of Nanoscience and Nanotechnology, 9, 5008–5013. Campbell, A., Araujo, J. A., Li, H., Sioutas, C., & Kleinman, M. (2009). Particulate matter induced enhancement of inflammatory markers in the brains of Apolipoprotein E knockout mice. Journal of Nanoscience and Nanotechnology, 9, 5099–5104. Hekmatara, T., Gelperina, S., Vogel, V., Yang, S.-R., & Kreuter, J. (2009). Encapsulation of water-insoluble drugs in poly(butyl cyanoacrylate) nanoparticles. Journal of Nanoscience and Nanotechnology, 9, 5091–5098. Oberdörster, G., Elder, A., & Rinderknecht, A. (2009). Nanoparticles and the brain: Cause for concern? Journal of Nanoscience and Nanotechnology, 9, 4996–5007. Pathak, S., Tolentino, R., Nguyen, K., D’Amico, L., Barron, E., Cheng, L., et al. (2009). Quantum dot labeling and imaging of glial fibrillary acidic protein intermediate filaments and gliosis in the rat neural retina and dissociated astrocytes. Journal Nanoscience and Nanotechnology, 9, 5047–5054. Sharma, H. S. (2007, December). Nanoneuroscience: Emerging concepts on nanoneurotoxicity and nanoneuroprotection. Nanomedicine, 2(6), 753–758. Review. Sharma, H. S. (2009a, June). Birth of a new journal. Journal of Nanoneuroscience. Sharma, H. S. (2009b). Nanoneuroscience: Nanoneurotoxicity and nanoneuroprotection. Journal of Nanoscience and Nanotechnology, 9, 4992–4995. Sharma, H. S., Ali, S. F., Dong, W., Tian, Z. R., Patnaik, R., Patnaik, S., et al. (2007, December). Drug delivery to the spinal cord tagged with nanowire enhances neuroprotective efficacy and functional recovery following trauma to the rat spinal cord. Annals of the New York Academy of Sciences, 1122, 197–218. Sharma, S., Ali, S. F., Hussain, S. M., Schlager, J. J., & Sharma, A. (2009). Influence of engineered nanoparticles from metals on the blood–brain barrier permeability, cerebral blood flow, brain edema and neurotoxicity. An experimental study in the rat and mice using biochemical and morphological approaches. Journal of Nanoscience and Nanotechnology, 9, 5055–5072.
ix Sharma, H. S., Ali, S. F., Tian, Z. R., Hussain, S. M., Schlager, J. J., Sjöquist, P.-O., et al. (2009). Chronic treatment with nanoparticles exacerbate hyperthermia induced blood–brain barrier breakdown, cognitive dysfunction and brain pathology in the rat. Neuroprotective effects of nanowired-antioxidant compound H-290/51. Journal of Nanoscience and Nanotechnology, 9, 5073–5090. Sharma, H. S., Ali, S., Tian, Z. R., Patnaik, R., Patnaik, S., Lek, P., et al. (2009). Nano-drug delivery and neuroprotection in spinal cord injury. Journal of Nanoscience and Nanotechnology, 9, 5014–5037. Review. Sharma, H. S., Patnaik, R., Sharma, A., Sjöquist, P.-O., & Lafuente, L. V. (2009). Silicon dioxide nanoparticles (SiO2, 40–50 nm) exacerbate pathophysiology of traumatic spinal cord injury and deteriorate functional outcome in the rat. An experimental study using pharmacological and morphological approaches. Journal of Nanoscience And Nanotechnology, 9, 4970–4980. Sharma, H. S., & Sharma, A. (2007). Nanoparticles aggravate heat stress induced cognitive deficits, blood–brain barrier disruption, edema formation and brain pathology. Progress in Brain Research, 162, 245–273. Review. Sharma, H. S., & Sharma, A. (2009, July). Conference scene: New perspectives on nanoneuroscience, nanoneuropharmacology and nanoneurotoxicology. Nanomedicine, 4(5), 509–513.
Acknowledgments I wish to express my sincere gratitude to Hilary Rowe, Cindy Minor, Susan Lee (USA), and Maureen Twaig (The Netherlands) during the initial development of this book project. I am indebted to Johannes Menzel, Lisa Tickner, and Lyndse Dixon (UK) for their untiring help through the incubation period of this book project on various aspects. My special thanks are due to Aruna Sharma (Sweden); Gayathri Venkatasamy (India), and Clare Caruana (UK) for all necessary help during preparation and editing of this volume.
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SECTION I
Nanodrug delivery and Imaging Techniques
H.S. Sharma (Ed.) Progress in Brain Research, Vol. 180 ISSN: 0079-6123 Copyright 2009 Elsevier B.V. All rights reserved.
CHAPTER 1
Drug delivery to the brain using colloidal carriers Jiang Chang1, Youssef Jallouli2, Alexandre Barras3, Nicole Dupont1 and Didier Betbeder1,4, 1
EA 2689, Laboratory of Physiology, IMPRT, University of Lille 2, 1 place Verdun, 59045 Lille, France EA 2648, Laboratory of the Blood Brain Barrier, IMPRT, University of Artois, rue Jean Souvraz, 62307 Lens, France 3 Interdisciplinary Research Institut, USR 3078 CNRS Parc Scientifique de la Haute Borne, 50 avenue de Halley – BP 70478, 59 658 Villeneuve d’Ascq, France 4 University of Artois, 62000 Arras, France
2
Abstract: Many neurodegenerative diseases, cancer, and infections of the brain become more prevalent as populations become older. Despite major advances in neuroscience, the blood–brain barrier (BBB) ensures that many potential therapeutics cannot reach the central nervous system (CNS). The BBB is formed by the complex tight junctions between the endothelial cells of the brain capillaries and their low endocytic activity. It results in the capillary wall that behaves as a continuous lipid bilayer and prevents the passage of polar substances. Drug delivery to the brain has remained one of the most vexing problems in translational neuroscience research, because of the difficulties posed by the BBB. Several strategies for delivering drugs to the CNS have been developed. This review rationalizes the strategies to target drugs to the brain by using different colloids. Keywords: nanoparticles; drug delivery; blood–brain barrier; colloid; targeting Introduction
of biologically active molecules to cross lipid membranes. For this reason the design and development of colloids containing bioactive agents for brain therapeutic application may be a resourceful approach to overcome limitations. Moreover, it is important to require a fundamental understanding of the in vivo interaction between the nanoparticles (NPs) and the blood–brain barrier (BBB).
Most of the intractable central nervous system (CNS) disorders have not been beneficially treated by classical small molecule therapy, including Alzheimer’s disease, the neurodegeneration of Parkinson’s disease, stroke, cerebral AIDS, brain cancer, the ataxias, the inherited inborn errors of metabolism, and other brain disorders. The diffusion of drugs from blood into the brain depends mainly upon the ability
The blood–brain barrier Progress in the brain drug delivery has lagged behind other areas in the molecular neuroscience, because of the difficulties posed by the BBB. An
Corresponding author. Tel.: þ33-320-626968; Fax: þ33-320-626963; E-mail:
[email protected] DOI: 10.1016/S0079-6123(08)80001-5
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overview of the BBB helps to elucidate the problems of drug delivery to the brain and to propose potential target to cross these barriers. In humans, there are approximately 650 km of capillaries perfusing the brain, and the surface area of the brain microvascular endothelium is approximately 20 m2 (Pardridge, 2003), which is 1000-fold greater than the surface area of either the blood–cerebrospinal fluid (CSF) barrier or the arachnoid membrane. Therefore, the quantitatively important barrier system within the brain is the BBB at the capillary endothelium. Despite the vast surface area of the human BBB, the thickness of the BBB is very thin (200–300 nm), and the total intracellular volume of the brain capillary endothelium is only 5 mL in the entire human brain. This very thin cellular barrier has some of the most restrictive permeability properties of any biological membrane (Oldendorf, 1971). The BBB provides the brain with nutrients, prevents the introduction of harmful blood-borne substances, and restricts the movement of ions and fluid to ensure an optimal environment for CNS. Meanwhile, BBB much more represents an
(a)
(b)
(c)
insurmountable barrier for the majority of drugs including anticancer agents, antibiotics, peptides, and other oligo- and macromolecular drugs. It is located at the level of the brain capillaries, where there is a convergence of different cell types: endothelial cells, pericytes, astrocytes, microglias (perivascular macrophages), and neurons. The brain microvessel endothelial cells that form the BBB display important morphological characteristics such as the presence of tight junctions between the cells, the absence of fenestrations, enzymes, high level of p-glycoprotein (P-gp) involved in drug efflux mechanisms, and a diminished pinocytic activity that together help to restrict the passage of compounds from the blood into the extracellular environment of the brain (Fig. 1). Thus, the BBB prevents the uptake of all large molecule drugs. Only small (with a molecular weight
