Nanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors

India

Preface

Prashant Kesharwani and Umesh Gupta

Brain tumors cause disruption to the selective properties of the vascular endothelia, even causing disruptions in the very selective blood–brain barrier, which are collectively referred to as the blood–brain barrier (BBB). Despite their low prevalence, brain tumors are one of the most lethal forms of cancer. Unfortunately, the BBB checks the permeation of most of the drugs across it, and hence, crossing this barrier is one of the most significant challenges in the development of efficient central nervous system therapeutics.

Over the last few years, several innovations in nanotechnology have made nanocarriers an attractive alternative for transporting drugs across the BBB. It is widely felt that nanotechnology will be the next industrial revolution. However, there is a clear need for innovative technologies to improve the targeting and delivery of therapeutics as well as diagnostic agents against brain tumors. Recent advancements in nanomedicine have made it possible to deliver chemotherapeutic agents to penetrate the impaired blood–brain-tumor barrier (BBTB) with coverage across the entire solid tumor and specific cell targeting, and to maximize the clinical benefit while limiting unwanted side effects.

Brain tumor capillaries overexpress certain receptors, which guide ligand-anchored nanocarrier-based drug delivery and facilitate drug delivery to brain tumor tissues. Nanocarriers involve either passive or active targeting for the drug or gene delivery at the site of cancerous cells or tissues. Passive targeting results in an attendant accumulation of drug or drug-carrier at a particular site. However, active targeting involves specific surface modification on carrier systems by active ligand, which guides its binding to a specific cell type, tissue, or organ with high affinity. In this regard, several features of nanocarriers, such as unique composition, desirable physicochemical properties, and small size favor passive targeting as well as surface functionality for active targeting, crafting them as a successful tool for the treatment of brain tumors.

This book provides an overview of different aspects of nanomedicine, which help will readers to design and develop novel drug delivery systems and devices that take advantage of recent advances in nanomedical technologies against brain tumors. The book consists of an introductory chapter on brain anatomy and brain tumors, followed by a discussion of the progress and challenges in delivering drugs across the BBB. Several chapters are devoted to the latest technologies and advances in nanotechnology and include practical solutions on how to design more effective nanocarriers for drug and gene delivery.

Focusing on the design, synthesis, and application of different nanocarriers in drug delivery against brain tumors, this book will be a valuable resource for graduates, pharmaceutical scientists, clinical researchers, and anyone working to tackle the challenges of delivering drugs in a more targeted and efficient manner against brain tumors. In totality, this book will prove to be one of the most comprehensive books available—combining both the fundamental pharmaceutical principles of nanocarriers along with the most important applications of nanotechnology in targeting and drug delivery to brain tumors. Featuring contributions from field experts and researchers in industry and academia, Nanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors provides state-of-the-art information on nanocarriers and their use in targeting, as well as drug delivery to brain tumors.

We hope this book will stimulate further interest in the drug delivery field, and that the readers of this book will find it useful.

Chapter 1

Tumors of the Central Nervous System

Anatomy and Interventional Considerations

Raviteja Suryadevara, Hassen Fadel, Sharon K. Michelhaugh, Sandeep Mittal and Prahlad Parajuli,    Wayne State University School of Medicine, Detroit, MI, United States

Abstract

Considered one of the deadliest forms of cancer, central nervous system (CNS) tumors are a diverse set of pathologic entities that manifest in different forms and regions of the brain and spinal cord. This chapter will (1) introduce the reader to the gross anatomy of the CNS and its spatial relationships; (2) examine CNS tumors in regards to their origins, classifications, and locations within the CNS; (3) describe current and alternative therapeutic methods that are commonly used or have been tested; and (4) briefly discuss the role of nanoparticles and their applications with regard to CNS tumors. By the end of this chapter, the reader will have gained a better understanding of the behavior of CNS tumors vis a vis their anatomical location in the CNS.

Keywords

CNS tumors; nanoparticles; CNS anatomy; brain tumor treatment; CNS tumor classification; spine tumors

Outline

1.1 Introduction 2

1.2 Cellular Composition of the CNS 2

1.2.1 The Neuron 2

1.2.2 Glial Cells 3

1.3 Gross Anatomy of the Human Brain 4

1.3.1 Spinal Cord 7

1.3.2 Brainstem 7

1.3.3 Diencephalon 9

1.3.4 Cerebellum 10

1.3.5 Hemispheres 11

1.3.6 Ventricular System 13

1.4 Barriers to the CNS 13

1.4.1 Blood–Brain Barrier 13

1.4.2 Blood–CSF Barrier 14

1.4.3 CSF–Brain Barrier 14

1.5 Brain Tumors 14

1.5.1 Tumors With Specialized Location of Incidence 15

1.5.2 Tumors Without Specific Location of Incidence 16

1.5.3 Metastatic Tumors 19

1.5.4 Current Treatment Modalities 20

1.6 Discussion 23

References 23

1.1 Introduction

In 2014, the estimated prevalence of central nervous system (CNS) tumors in the United States was 162,341 cases (Howlader et al., 2017). By 2017, there was an estimated incidence of CNS tumor cases of 23,800. At first glance, CNS tumors may seem less significant, especially considering they are ranked 16th among the most common types of cancer. However, these cancers have an extremely high mortality rate at nearly 70%, making CNS neoplasms one of the deadliest forms of solid tumors with a poor prognosis. Additionally, studying this type of cancer is difficult given that only 33% of patients survive a 5-year period and biopsies of CNS unique tumors present difficulties, resulting in a dearth of knowledge in areas such as pediatric CNS tumors (Bondy et al., 2008). For these reasons, there is a continuous drive to develop new forms of treatment and therapies to improve the outcomes of CNS cancer patients, however, alternative treatment methods, such as nanoparticle therapy, hold promise.

CNS tumors are a diverse set of pathologic presentations that manifest in different forms and regions of the brain. This chapter will (1) introduce the reader to the cell biology and gross anatomy of the CNS, including spatial relations; (2) examine CNS tumors in regards to their origins, classifications, and locations within the CNS; (3) describe current and alternative therapeutic methods that are commonly used or have been tested; and (4) examine briefly the role of nanoparticles (NPs) and their applications with regard to CNS tumors. By the end of this chapter, the reader will have gained a better understanding of the behavior of CNS tumors while potentially developing new ideas for the role nanoparticle therapy can play in combating CNS tumors.

1.2 Cellular Composition of the CNS

1.2.1 The Neuron

The functional unit of the nervous system is the neuron. Although a number of types of neurons exist throughout the nervous system, serving equally diverse and numerous functions, each neuron is made up of the same basic components: a cell body and nucleus with a single axon and attached dendrites. The cell body (soma) of the neuron is made up of a large round nucleus containing a prominent nucleolus, surrounded by a cytoplasm (perikaryon). Connected to one pole of the cell body is the axon, a tubular extension of the soma that is responsible for the anterograde transmission of electrical impulses. At the junction of the axon proper and the cell body is the axon hillock, a specialized region of the neuron that integrates and summates impulses from the soma and subsequently propagates those impulses along the axon. The distal end of the axon is made up of a variable number of terminal buttons, swellings that chemically communicate with other neurons or target organs. On the opposite pole of the neuron are the dendrites. In contrast to the role of the axon as the dispatcher of neural impulses, dendrites are highly branched, nonaxonal extensions of the soma that receive electrical impulses from neurons or the environment. By receiving and directing impulses toward the soma, dendrites effectively work as the arbiters and collectors of incoming neuronal communications. The junction at which the axon of one neuron communicates with either an effector organ or the dendrites of another neuron is called the synapse. Neurons are considered terminally differentiated and therefore do not divide in adulthood (Bear & Paradiso, 2007). Because of the lack of proliferative potential, neuronal-derived tumors are infrequent and treatment usually results in full recovery (Shin et al., 2002).

1.2.2 Glial Cells

The glial cells of the nervous system are a group of nonsynaptic support cells that function to maintain an optimal parenchymal microenvironment for neuronal function (Bear & Paradiso, 2007). Glial cells make up the majority of cells in the nervous system and are integrally involved in the development, maintenance, and repair of neuronal tissue. Astrocytes, oligodendrocytes, ependymal cells, and microglia are the glial cells of the CNS. Glial cells retain the ability to proliferate and thus give rise to the majority of tumors of both the central and peripheral nervous system (PNS) (Bear & Paradiso, 2007).

Astrocytes are highly branched and metabolically active cells that provide functional, mechanical, and protective support to the neurons of the brain and spinal cord (Bear & Paradiso, 2007). The structural support of astrocytes is also highlighted by the glial limitans, a continuous covering of the entire surface of the brain and spinal cord made up of the fused distal ends (endfeet) of astrocyte extensions (Bear & Paradiso, 2007). Astrocyte endfeet also line every blood vessel in the CNS, further isolating the CNS from the external environment and contributing to the formation of the blood–brain barrier (BBB) (Engelhardt & Sorokin, 2009). Beyond structural support, astrocytes also play an integral role in response to CNS damage. Following injury and subsequent destruction of liable nervous tissue, astrocytes proliferate and form a lasting scar that works to protect surrounding viable tissue from the inflamed and necrotic milieu of the damaged area (Sofroniew & Vinters, 2010). Ancillary to the support and protective roles discussed, astrocytes also have essential metabolic activities including electrolyte metabolism, neurotransmitter regulation, and energy storage. Due to their vast proliferative and metabolic activity, astrocytes give rise to the majority of CNS tumors, including the most common and fatal adult primary malignancy of the CNS, glioblastoma (GBM) (Gladson, Prayson, & Liu, 2010) (GBM has the prefix glio-, which indicates a glial-derived tumor).

Another type of CNS glial cell is the oligodendrocyte. Derived from neuroectoderm, oligodendrocytes are responsible for myelinating axons of CNS neurons. As the predominant cell in the white matter, oligodendrocytes are a major source of oligodendrogliomas commonly arising in the frontal and temporal lobes (Van den Bent, Reni, Gatta, & Vecht, 2008).

Microglia are the primary immune effector cells of the CNS. Derived from myeloid progenitor cells of the yolk sac, microglia serve as the CNS parallel to peripheral macrophages, and are thus the chief mediators of CNS inflammatory reactions. With long and highly branched processes extending from the cell body, microglial cells remain quiescent in the absence of CNS insult, maintaining a basal-level scavenger and surveillance role. However, in response to foreign pathogens and pathological processes, microglia activate by morphologically transforming and proliferating rapidly, ultimately migrating to the site of CNS damage to serve as the initial and primary immunological defense of the CNS (Lull & Block, 2010). Although the role of microglial cells is largely protective, it should be noted that constant and excessive activation of microglial cells can be detrimental to the CNS, as best characterized by the inflammatory and neurotoxic effects of microglia that contribute to the pathology of diseases such as Alzheimer’s disease (Lull & Block, 2010).

The last type of glial cell in the CNS is ependymal cells. Derived from neural ectoderm, ependymal cells line the ventricular and central canal surface of the brain and spinal cord, respectively. The ependymal cells are attached to one another by desmosomes, forming a simple cuboidal epithelium with apical cilia and microvilli that function to facilitate the circulation of cerebrospinal fluid (CSF) throughout the ventricular system (Del Bigio, 2010) (see 1.3.6 Ventricular System, under Gross Anatomy of the Human Brain). The ependymal cells also give rise to the epithelium of the choroid plexus, a highly vascularized, villous collection of cells that produce the CSF that occupies the ventricular system (Del Bigio, 2010). Tumors of ependymal cells are termed ependymomas and represent a common childhood malignancy that can lead to life-threatening CSF blockades (hydrocephalus) and subsequent mass effects (Del Bigio, 2010). Additionally, tumors of the choroid plexus are classified as choroid plexus tumors (Jaiswal et al., 2013) (Table 1.1).

Table 1.1

The support cells of the PNS are Schwann cells and satellite cells (Bear & Paradiso, 2007). Although the role of satellite cells is currently being investigated, what is known is that satellite cells sheath the cell bodies of neurons located in the ganglia of the PNS (Catala & Kubis, 2013). Therefore, satellite cells function similarly to CNS astrocytes. Conversely, the role of Schwann cells in the PNS has been established. Analogous to the role of oligodendrocytes in the CNS, Schwann cells are responsible for the myelination of all PNS axons. However, unlike oligodendrocytes, Schwann cells are derived from neural crest cells and are also responsible for providing structural and functional support to unmyelinated axons of the PNS. Because of the added structural support of Schwann cells, PNS axons have a far greater capacity to partially repair and regenerate following neural insults (Catala & Kubis, 2013). The importance of Schwann cells is highlighted by the consequences of the disease states that target Schwann cell activity or myelination. Schwann cell tumors are termed schwannomas, of which the most well-known schwannoma is the vestibulocochlear schwannoma that consistently forms at the cerebellopontine angle (see Section 1.3.2) (Kurtkaya-Yapicier, Scheithauer, & Woodruff, 2003).

1.3 Gross Anatomy of the Human Brain

The human nervous system is divided into two anatomical divisions: the CNS, consisting of the brain and spinal cord, and the PNS made up of all spinal and cranial nerves (CN) that branch to connect the CNS to peripheral structures. The vast majority of primary and metastatic nervous system tumors are confined to the CNS due to anatomical and cellular barriers, which are discussed below. Our understanding of the organization of the CNS and these barriers allows us to design optimal nanoparticle therapies.

1.3.1 Spinal Cord

Considered the primary avenue for the distribution of afferent and efferent signals to and from the brain, the spinal cord is housed inside the vertebral canal created by the spinal vertebrae. These vertebrae and the respective regions of the spinal cord that exist there are divided into four regions rostrally to caudally: cervical, thoracic, lumbar, and sacral (Bear & Paradiso, 2007) (Fig. 1.1). The boundaries include the caudal medulla (see Section 1.3.2) superiorly, and inferiorly the spinal cord terminates as the filum terminale, a common location of ependymomas (Bear & Paradiso, 2007; Yao, Mack, & Taylor, 2011). Along the length of the spinal cord, there are ventral and dorsal roots, which conduct efferents and afferents to and from the PNS, respectively. Surrounding the spinal cord are three layers of tissue called the meninges which function to protect the spinal cord and house the CSF. From outermost to innermost, these layers are: the dura mater, arachnoid mater, and pia mater, which overlie the spinal cord itself. Between the arachnoid and pia exists the subarachnoid space, where the CN and vascular structures reside surrounded by CSF. Note that these meninges layers are found throughout the entire CNS, including the brain, and thus present a great variety of meningiomas (tumors derived from the meninges) (Alahmadi & Croul, 2011; Bear & Paradiso, 2007). Blood supply to the spinal cord is provided primarily by the vertebral arteries and the medullary branches arising from the aorta (Purves et al., 2001).

Figure 1.1 Anatomical divisions of the spinal cord.

1.3.2 Brainstem

The brainstem is arranged caudal to rostral in the following order: the medulla oblongata (medulla), pons, and midbrain. Containing various ascending and descending sensory and motor tracts, as well as the nuclei of CN III through XII, the brainstem is the center for the generation, transmission, and integration of sensory, motor, and autonomic information.

The medulla, derived from the myelencephalon, is the most caudal portion of the brainstem and is continuous with the spinal cord at the level of the foramen magnum. The dorsal portion of the rostral medulla also forms part of the floor of the fourth ventricle, which tapers caudally to eventually form the central canal of the spinal cord. Melanocytic tumors are known to occur in this region of the brainstem (Kusters-Vandevelde et al., 2015). The blood supply to the medulla is provided by the posterior inferior cerebellar artery, the anterior spinal artery, and the branches of the vertebral artery (Purves et al., 2001).

The part of the brainstem rostral to the medulla is the pons. Lying between the medulla caudally and the midbrain rostrally, the pons is an intermediary between the cerebellum and the cerebrum, a conduit for ascending and descending pathways, and the location of multiple cranial nerve nuclei. The pons is located at the level of the cerebellum and their margins form the cerebellopontine angle, an exit point for the 7th (facial) and 8th (vestibulocochlear) CN. This junction is of particular clinical importance as tumors in this area, predominantly vestibular schwannomas, lead to specific and insightful clinical findings of hearing loss, tinnitus, and unsteady gait due to CN VIII impairment as well as cerebellar compression by mass effect. The dorsal aspect of the pons together with the medulla forms the rhomboid fossa, which corresponds to the floor of the fourth ventricle (Bear & Paradiso, 2007). The blood supply to the pons is predominately supplied by the superior cerebellar artery as well as the pontine branches of the basilar artery (Purves et al., 2001).

Extending rostral from the pons is the midbrain. Derived from the mesencephalon, the midbrain is the most rostral part of the brainstem and acts as the conduit between the cerebrum and the rest of the brain stem. Along the axial plane, the midbrain can be divided into three segments: the dorsal tectum, the intermediately located tegmentum, and the ventral crus cerebri (Bear & Paradiso, 2007). The dorsal tectum is characterized by the inferior and superior colliculi, two pairs of protuberances that are involved in auditory and visual processing, respectively. Ventral to the tectum is the tegmentum, which is the rostral continuation of the pontine tegmentum. Between the tectum dorsally and the tegmentum ventrally is the cerebral aqueduct, a ventricular channel that connects the third and fourth ventricles. Blood supply to the midbrain is derived from the posterior and superior cerebral arteries as well as branches of the posterior communicating artery and the anterior choroidal artery (Purves et al., 2001) (Fig. 1.2).

Figure 1.2 Sagittal view of the brain and relevant structures of the brainstem.

1.3.3 Diencephalon

The diencephalon, derived from the prosencephalon and located between the cerebral cortex and brainstem, is a paired structure subdivided into the thalamus, ventral thalamus, hypothalamus, and epithalamus (Bear & Paradiso, 2007). With its extensive cortical and subcortical connections, the diencephalon is the integrative epicenter for the majority of sensory, motor, and limbic impulses (Bear & Paradiso, 2007). The diencephalon is divided at the midline into symmetrical structures by the third ventricle, which connects to the lateral ventricles via the interventricular foramina of Monro as well as caudally to the cerebral aqueduct. The entire diencephalon is supplied largely by the branches of the posterior cerebral arteries (Purves et al., 2001). Due to its extensive role in conduction of information, homeostasis, and endocrine function, the diencephalon presents a difficult target for tumor therapy.

The thalamus is an oval-shaped collection of nuclei that serves as the primary relay center for motor, sensory, and limbic pathways. As the largest component of the diencephalon, the thalamus has extensive and reciprocal connections to the cerebral cortex, with essentially each thalamic nucleus having efferent and afferent projects to a particular part of the cerebral cortex. The thalamus also has a vast array of inputs from virtually every sensory, motor, cerebellar, and limbic pathway, and subsequently projects these inputs to the appropriate part of the cortex. Therefore, the thalamus principally acts as a gateway for inputs to communicate with and be modified by particular areas of the cortex.

The hypothalamus contrasts the thalamus’s somatic functions by acting as the neural center for the homeostatic and endocrine control of the body. The functions of the hypothalamus are achieved by having neurons capable of monitoring and responding to deviations in a variety of tightly regulated bodily targets such as temperature, hunger, sleep, etc. Another fundamental role of the hypothalamus is the regulation of the pituitary gland (neurohypophysis), the principal neuroendocrine gland of the body located in the hypophyseal fossa of the sella turcica in the sphenoid bone (Bear & Paradiso, 2007). Hypothalamus function is greatly affected by histiocytic tumor activity, i.e., Langerhans cell histiocytosis (Grois, Prayer, Prosch, & Lassmann, 2005).

The next portion of the diencephalon is the ventral thalamus (subthalamus). As an integral part of the basal ganglia, the ventral thalamus receives input from the motor cortex of the cerebrum as well as the globus pallidus (external) and projects back to the globus pallidus (internal) and to the substantia nigra. Therefore, the ventral thalamus is a principal actor in the control and function of motor movement.

The last part of the diencephalon is the epithalamus, which consists of the pineal gland, habenular nuclei, and the stria medullaris thalami. The pineal gland in particular is a small, cone-shaped, and richly vascularized structure located at the base of the third ventricle at the midline, extending superiorly over the superior colliculi (Bear & Paradiso, 2007). Arising as an outpouching of the diencephalon, the pineal gland is made up of pinealocytes that synthesize melatonin in response to indirect retinal stimulation of the suprachiasmatic nucleus of the hypothalamus. Therefore, the pineal gland’s melatonin production plays an integral role in the establishment and maintenance of the circadian rhythm. Tumors that occur here are collectively classified as tumors of the pineal region and may cause obstructive hydrocephalus (Fang & Meyers, 2013; Mandera, Bazowski, Wencel, & Dec, 1999).

1.3.4 Cerebellum

Derived from the metencephalon, the cerebellum is located posterior to the brainstem and ventral to the tentorium cerebelli, occupying the majority of the posterior fossa. The cerebellum has two hemispheres, each with two surfaces that together form a wedge-shaped structure: the superior surface that interfaces with the tentorium cerebelli and the inferior surface that follows the contour of the occipital bone. The cerebellum is anatomically divided into three lobes: the anterior, posterior, and flocculonodular lobes. The posterolateral fissure separates the flocculonodular lobe from the anterior and posterior lobes, while the primary fissure separates the anterior and posterior lobes from one another. With extensive efferent connections to the cerebrum, thalamus, spinal cord, and brainstem, the cerebellum is heavily involved in the influence of motor movements by controlling and adjusting motor outputs to maintain steady movement and posture (Bear & Paradiso, 2007). The occurrence of specific tumors, e.g., hemangioblastomas, produces von Hippel-Lindau syndrome (Wanebo, Lonser, Glenn, & Oldfield, 2003). The blood supply to the superior surface of the cerebellum is provided by the superior cerebellar artery, while blood supply to the inferior surface of the cerebellum is provided by the inferior cerebellar arteries (Purves et al., 2001).

1.3.5 Hemispheres

The cerebrum, derived from the prosencephalon and composed of two cerebral hemispheres, is the largest part of the human brain. The outer layer of the cerebrum is the cerebral cortex and is characterized by elevated ridges (gyri) parted by depressions (sulci). Separated by the longitudinal cerebral fissure, the two cerebral hemispheres are composed of six lobes separated into: frontal, parietal, temporal, occipital, limbic, and insular—with all but the insular lobe visible from the surface of the cortex (Fig. 1.3). Each lobe can be anatomically separated from the other by major cortical sulci or by imperceptible lines that connect anatomical landmarks. Connecting the two cerebral hemispheres is the corpus callosum, the largest bundle of fibers in the brain, which functions to connect each area of the cortex of one hemisphere to the mirrored or functionally related cortical area of the opposite hemisphere (with few exceptions). The blood supply to each area of the cortex differs, with most areas receiving blood from multiple arteries.

Figure 1.3 Lobes of the cortex.

The frontal lobe is the largest of the six lobes and is housed within the anterior cranial fossa. On the lateral surface of the cortex, the frontal lobe is separated from the parietal lobe by the central sulcus and separated from the temporal lobe by the lateral sulcus (Sylvian fissure). On the medial, sagittal aspect of the cortex, the medial continuation of the central sulcus separates the frontal lobe from the medial parietal lobe and the cingulate sulcus separates the frontal lobe from the cingulate gyrus and limbic lobe. The inferior surface of the frontal lobe is divided by the olfactory sulcus, in which the olfactory bulb (first-order olfactory sensory neurons) and tract are located, into the medial gyrus rectus and the lateral orbital gyri. Overall, the frontal lobe is associated with higher-level processing and executive decision-making. The blood supply to the frontal lobe is largely provided by the anterior and middle cerebral arteries and their branches (Purves et al., 2001).

The parietal lobe is located rostral to the occipital lobe and caudal to the frontal lobe. The central sulcus separates the parietal lobe from the frontal lobe. Less distinctly, the parieto-occipital sulcus and an imaginary line between the end of the sulcus and the preoccipital notch on the lateral margin of the hemisphere separates the parietal lobe from the occipital lobe. The parietal lobe is the location of both primary and secondary somatosensory cortices, and thus its function is to receive somatosensory afferents from the body, i.e., pain, temperature, and proprioception, and to process them. The blood supply to the parietal lobe is provided by the anterior, middle, and posterior cerebral arteries and their respective branches (Purves et al., 2001).

The occipital lobe, the smallest segment of the cortex, forms the most caudal portion of the cerebral hemisphere. Rather than having distinct anatomical boundaries, the occipital lobe is separated from the parietal lobe rostrally and temporal lobe laterally by the parieto-occipital sulcus and an imaginary line between the end of the sulcus and the preoccipital notch. As its name implies, the occipital lobe functions as the cerebral visual processing center. The blood supply to the occipital lobe is largely derived from the branches of the posterior cerebral artery (Purves et al., 2001).

The temporal lobe is located at the lateral and inferior aspects of the cerebral hemisphere. Occupying the majority of the middle cranial fossa, the temporal lobe is bounded superiorly by part of the lateral sulcus and an imaginary line connecting the lateral sulcus to the imaginary line connecting the parieto-occipital sulcus to the preoccipital notch (Bear & Paradiso, 2007). The caudal boundary of the temporal lobe is the line between the terminal end of the parieto-occipital sulcus and the preoccipital notch. The inferior and rostral boundaries of the temporal lobe are formed by the middle cranial fossa (Bear & Paradiso, 2007). The temporal lobe is largely responsible for speech, auditory processing, and memory. Neuronal tumors have often been localized to this lobe, producing symptoms of receptive aphasia (Bear & Paradiso, 2007; Shin et al., 2002). The blood supply to the temporal lobe is mainly derived from the middle cerebral artery (Purves et al., 2001).

Located deep to the lateral fissure is the insular lobe. As the only part of the cerebral cortex not visible at the surface, but examined by removing the anterior aspect of the parietal lobe (operculum), the insular lobe is made up of multiple gyri that are divided by the central insular sulcus. This lobe is primarily responsible for higher-level auditory processing and integration of olfactory and gustatory sensory information. The blood supply to the insula is provided by branches of the middle cerebral artery (Purves et al., 2001).

The limbic lobe, an integral part of the limbic system, is composed of the subcallosal area, cingulate gyrus, parahippocampal gyrus, and the uncus. The cingulate sulcus, colossal sulcus, and collateral sulcus separate the limbic lobe from both adjacent cortical areas and the corpus callosum. Rather than operating as a lobe serving a singular function, the limbic cortex is involved in a variety of extensive and complex processes such as learning, memory, emotion, and behavior. The limbic lobe’s blood supply is derived from the anterior and posterior cerebral arteries as well as the anterior choroidal artery (Purves et al., 2001).

1.3.6 Ventricular System

The ventricular system is primarily responsible for circulating CSF throughout the CNS. This system consists of seven components: choroid plexus, two symmetrical positioned lateral ventricles, third ventricle, cerebral aqueduct, fourth ventricle, and the central canal of the spinal cord.

First, cells of the specialized choroid plexus epithelia create the CSF. The choroid plexus is located in the lateral ventricle (except the occipital and frontal horns), the roof of the third ventricle, and the roof of the fourth ventricle. To understand the flow of CSF, we will assume the case in which CSF is produced in the lateral ventricles. After production, the CSF moves from the lateral ventricles into the third ventricle through the two intraventricular foramina of Munro. From the third ventricle, the CSF flows into the fourth ventricle through the cerebral aqueduct. From the fourth ventricle, the CSF exits the cranium and enters the subarachnoid space of the spinal cord and the brain through two lateral apertures (foramina of Luschka) and a single median aperture (foramen of Magendie). The fourth ventricle is also continuous with the central canal of the spinal cord, the last component of the ventricular system. Because it is a location where the majority of CSF is evenly distributed, tumors in the fourth ventricle, such as ependymomas, medulloblastomas, and choroid plexus tumors, can cause complications with the flow of CSF, resulting in a condition known as obstructive or communicating hydrocephalus. After its journey through the respective subarachnoid regions of the CNS, the CSF is reabsorbed into the venous system at the superior sagittal sinus, located at the margin of the falx cerebri, through structures known as arachnoid granulations. Complications that arise with CSF reabsorption generally cause a condition known as nonobstructive or communicating hydrocephalus.

1.4 Barriers to the CNS

The CNS is isolated from any direct, intimate contact with other body systems through various barriers. These barriers act to protect the CNS from infectious pathologies as well as create compartments for separation of fluids. Understanding these barriers can allow one to design therapies that can potentially overcome them when necessary.

1.4.1 Blood–Brain Barrier

The BBB is found between the lumen of blood vessels found in the CNS and the parenchyma of the brain. The endothelial cells found in this barrier form adherens junctions and tight junctions, specialized junctional complexes that prevent the direct passage of fluids but allow for selective diffusion, with each other to form the core of the BBB. Other cell types found in this region are astrocytes and pericytes. Astrocytes are a heavily debated topic in regard to the influential role they play in the development of the BBB. However, astrocyte cross-talk with endothelial cells has been demonstrated (Engelhardt & Sorokin, 2009). This signaling is thought to be responsible for modulation of arteriole dilation in a calcium-dependent manner and regulation of tight-junction formation, presenting potential targets for drug delivery. Pericytes are primarily found at the interface of microvessels (Ballabh, Braun, & Nedergaard, 2004). They are implicated in the maintenance of the integrity of microvessels as well as in angiogenesis and differentiation of microvessel cells (Ballabh et al., 2004).

1.4.2 Blood–CSF Barrier

This barrier is found at the interface between the choroid plexus and the vessels that supply it. However, unlike the BBB, the capillaries found near the choroid plexus are fenestrated, lacking tight endothelial junctions. Therefore, this barrier is created by the apical choroid plexus epithelial cells, which form the necessary tight junctions. The arachnoid membrane of the meninges is also considered a part of this barrier as it separates the CSF from blood vessels and can actively modify the CSF composition (Engelhardt & Sorokin, 2009). There are active transport systems which are capable of efflux of specific solutes, such as iodine and thiocyanate, which can be competitively inhibited by perchlorate (Engelhardt & Sorokin, 2009). These transport mechanisms are important when considering avenues for drug delivery.

1.4.3 CSF–Brain Barrier

The CSF–brain barrier is found in the brain’s ventricular system and the central canal of the spinal cord. The predominant cell type found at this barrier is ependymal cells. These cells form a unique junction called strap junctions along with adherens junctions and gap junctions, which allow for cell-to-cell communication (Whish et al., 2015). Strap junctions have been demonstrated to morph with the normal course of embryonic and fetal development, also continuing into adult life. These changes are important to note because the diffusive properties of the barrier alter as the organism ages. Specifically, it has been demonstrated in mice that early during development these junctions generally permit particles of 286 Da to diffuse freely, whereas later in development the size allowed increases to 70 kDa, allowing for more direct access to the brain parenchyma (Whish et al., 2015).

1.5 Brain Tumors

This section examines the common types of brain tumors, their locations of incidence, and special characteristics they may possess. The section is divided into two parts: (Section 1.5.1) tumors with specialized localization of incidence and (Section 1.5.2) tumors with unspecific localizations of incidence. Tumors that derive in the CNS are primary tumors of the CNS, whereas tumors that are caused by migration of tumors to the CNS are termed secondary, metastatic tumors. Lastly, current and alternative treatment modalities for brain tumors will be introduced.

1.5.1 Tumors With Specialized Location of Incidence

The following tumors are associated with specific regions of the CNS.

1.5.1.1 Choroid Plexus Tumors

As the name suggests, choroid plexus tumors are tumors that arise from cells that form the epithelium of the choroid plexus, where CSF is produced. To review, the choroid plexus is found in all components of the ventricular system except the cerebral aqueduct, frontal horn of the lateral ventricle, and the occipital horn of the lateral ventricle (Jaiswal et al., 2013). For all tumor types, see Table 1.1.

1.5.1.2 Pineal Gland Tumors

Pineal gland tumors are derived from the epithelium of the pineal gland, which is located at the base of the third ventricle (Fig. 1.4). Because of the gland’s role in regulation of melatonin levels, tumors in this region can have far-reaching effects on circadian rhythm (Mandera et al., 1999). Pineal parenchymal tumors in particular display unique calcifications that can be detected easily by conventional imaging methods (Fang & Meyers, 2013). Also, pineoblastomas are prone to restricted diffusion, so they will appear hyperdense on magnetic resonance imaging (MRI) (Fang & Meyers, 2013).

Figure 1.4 Tumors of localized incidence. Tumor regions are circled.

1.5.1.3 Embryonal Tumors

This tumor type generally occurs in infants and children when embryonic cells remain in the brain after birth and continue to divide mitotically. These embryonic cells can also migrate via CSF to other regions of the CNS (Board, 2017). Medulloblastomas are derived from the cells of the cerebellum, and are generally localized to the fourth ventricle. Nonmedulloblastoma embryonal tumors generally arise in the cerebrum (Board, 2017). These are much more difficult to localize, but they present a constellation of symptoms which can be used to determine the approximate location of the tumor.

1.5.1.4 Tumors of the Sellar Region

The sellar region is the region of the brain containing the pituitary gland. It is inferior to the optic chiasm and rostral to the third ventricle (Fig. 1.4) (Bear & Paradiso, 2007). A unique tumor subtype of this region is the craniopharyngioma, which is an expansion of the pituitary gland into the brain (Jagannathan, Kanter, Sheehan, Jane, & Laws, 2007). This type of tumor is embryological in origin, specifically during the formation of the pituitary gland itself (Jagannathan et al., 2007). However, unlike other embryological tumors, it does not migrate to other regions of the brain (Jagannathan et al., 2007). Additionally, it can cause compression of the optic nerves or optic chiasm located superiorly to it, presenting with unique vision defects.

1.5.2 Tumors Without Specific Location of Incidence

1.5.2.1 Gliomas

Gliomas are one of the most common types of primary tumors found in the CNS, comprising more than 30% of all CNS tumors. Gliomas are further divided into individual subtypes depending on the type of glial cell each tumor derives from: astrocytomas (astrocytes), oligodendrogliomas (oligodendroglia), and ependymomas (ependymal cells).

Astrocytomas are the most common type of glial brain tumor and are further divided into four grades: pilocytic astrocytoma (WHO grade I, benign), diffuse astrocytoma (WHO grade II, some cellularity, no mitotic activity), anaplastic astrocytoma (WHO grade III, definitive cellularity, mitotic,), GBM (WHO grade IV, most malignant, microvascular proliferation evident) (Louis et al., 2016). Pilocytic astrocytomas are commonly localized to the cerebellum, optic pathway, and dorsal brainstem (Sievert & Fisher, 2009).

Oligodendrogliomas are the second most common type of glioma. They are slow-growing tumors which take several years to develop completely (Wesseling, van den Bent, & Perry, 2015). They possess a diffusive infiltration mechanism and commonly accumulate near the pia mater, neurons, or microvessels (Wesseling et al., 2015). They possess a unique quality of calcification, which allows for ease in radiological localization of these tumors (Van den Bent et al., 2008). However, there are no exact regions where these tumors arise. These tumors are assessed on a grading scale similar to that described for astrocytomas (Louis et al., 2016).

Finally, ependymomas are tumors that arise from the ependymal cells which line the ventricles and central canal, forming the CSF–brain barrier (Del Bigio, 2010). Although these tumors can occur anywhere in the ventricular system that ependymal epithelium is found, they are commonly traced to the fourth ventricle and to a lesser extent the central canal or the filum terminale (Yao et al., 2011).

1.5.2.2 Neuronal and Mixed Neuronal-Glial Tumors

Pure neuronal cell tumors are commonly referred to as gangliocytomas, where the only cell type that this tumor is derived from is the neuron (Shin et al., 2002). Glial cells do not contribute to the neoplastic nature of the tumor. These tumors are commonly found anywhere in the cerebral hemispheres or the cervicothoracic spinal cord. Within the cerebral hemispheres, they are commonly localized to the temporal lobe or both the temporal and frontal or parietal lobes. Other locations include the cerebellum, hypothalamus, pineal region, and, less commonly, the sellar region (Shin et al., 2002).

Gangliogliomas are a rare type of mixed neuronal-glial tumor in the CNS. These tumors are frequently localized to the temporal lobe. It is important to note here that this tumor type is difficult to distinguish from pure neuronal due to a wide spectrum of neoplasticity found in the glial cells (Shin et al., 2002).

1.5.2.3 Tumors of the Cranial and Paraspinal Nerves

Broadly, these tumors are derivatives of the components of the PNS, specifically the components that form the peripheral nerve sheath. Thus, the subtypes include schwannomas (Schwann cells), neurofibromas, nerve sheath tumors, and perineuriomas. The most common of these are schwannomas, which develop from the Schwann cell of the peripheral nerve sheath (Kurtkaya-Yapicier et al., 2003). This type of tumor is difficult to diagnose and is commonly misdiagnosed as other types of tumors or incorrectly assessed in its severity.

1.5.2.4 Meningiomas

Another common primary intracranial brain tumor, meningiomas are tumors that are derived from the meninges. These tumors are assessed based on their histological architecture and assigned a WHO grade (I–III). Currently, there are 15 different histologic subtypes, of which nine are grade I, three are grade II, and three are grade III (anaplastic) (Alahmadi & Croul, 2011). These tumors are also assessed on their ability to infiltrate brain tissue, mitotic activity, growth pattern, cellular density, and the presence of necrosis. In theory, these tumors can occur anywhere the meninges are present; however, their exact location can be determined based on the clinical presentation of symptoms.

1.5.2.5 Mesenchymal, Nonmeningothelial Tumors

Mesenchymal, nonmeningothelial tumors are derived from the mesenchymal stem cells, but are not associated with meningeal epithelia. Because they are not related to the epithelia, but are derivative of the underlying connective tissue or nonepithelial tissue, these tumors are commonly classified as types of sarcomas. Of specific importance are two types: solitary fibrous tumors (SFTs) (hemangiopericytoma (HPC); note: SFTs is the more commonly accepted name) and hemangioblastoma.

SFTs are considered the most prevalent form of mesenchymal tumor (Penel, Amela, Decanter, Robin, & Marec-Berard, 2012). There are two clinically recognized nonmeningeal forms: pleural SFT and soft-tissue SFT (Penel et al., 2012). Pleural SFTs are considered true HPCs and include tumors of myoid and pericytic differentiation. Soft-tissue tumors include lesions that possess some features of HPCs, but not all. This can sometimes result in misdiagnosis. According to the WHO, this type of tumor is considered malignant when it possesses hypercellular, mitotic activity (Penel et al., 2012). No definitive region of occurrence has been noted.

Hemangioblastomas are mesenchymal tumors that originate in the vessels of the CNS. This type of tumor predominantly implicates the cerebellum (Lindau tumors, associated with von Hippel-Lindau disease) and the spinal cord. Occurrence has also been noted, although extremely rarely, in the supratentorial (superior to the cerebellum) compartment, optic nerve, and peripheral nerves (Wanebo et al., 2003).

1.5.2.6 Melanocytic Tumors

Melanocytic tumors are derived from melanocytes. These cells migrate during embryogenesis and populate the skin as well as mucosal surfaces, the urogenital tract, and the leptomeninges (the inner two meningeal layers—arachnoid and pia) (Kusters-Vandevelde et al., 2015). Concentrated populations of melanocytes of the leptomeninges are typically found at the ventrolateral surface of the medulla and the cervical regions of the spinal cord. According to the WHO, the current spectrum of primary melanocytic tumors ranges from melanocytotic (most benign), to melanocytoma, melanoma, and melanomatosis (most malignant) (Louis et al.,