**2. Understanding WHO Classification of CNS tumors**

Gliomas are the most frequent, very diverse group of intrinsic tumors of the central nervous system and are conventionally classified in harmony to their microscopic alikeness with recognized cells of origin according to glial precursor cell families. Major groups consist of diffuse gliomas, categorized by widespread growth into the adjoining CNS parenchyma, and more confined "nondiffuse" gliomas, with pilocytic astrocytoma and ependymomas [6]. The fourth edition of the WHO Classification of CNS tumors published in 2016 has essentially changed the classification of diffuse gliomas. These tumors are presently defined based on presence/absence of IDH mutation and 1p/19q codeletion. It can be attributed to massive expansion of knowledge on molecular alterations in tumors of the central nervous system (CNS) [2]. Until now, tumors were defined based on their histology. Any molecular information was mainly provided as supplementary information within histologically defined categories. Current advances in the molecular conceptualization of gliomas recommend some probable reasons for the failure of targeted therapies in gliomas. Specially, the histologic-based glioma categorization comprises of multiple molecular subtypes with discrete biology, usual history, and diagnosis. These observations have resulted in improvement in diagnosis and classification by the World Health Organization [7]. These perceptions regarding glioma biomarkers and subtypes highlight several clinical challenges. Firstly, the field is witnessing the struggle of reconsidering the results of previous studies and retrospective data using the new classifications to explain prognostic assessments and treatment recommendations for patients. Secondly, the new classification requires changes in the design and stratification of future clinical trials. Hence, these observations offer the required framework for the growth and evaluation of novel targeted therapies for specific glioma subtypes [2, 8].

Drug delivery to tumor can be monitored using nuclear medicine imaging techniques like single-photon emission computed tomography (SPECT),

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**agents**

*Radiolabelled Nanoparticles for Brain Targeting DOI: http://dx.doi.org/10.5772/intechopen.92668*

improved the resolution to millimeter level [11].

scan in order to determine path of diffusion of tracer.

can be overcome by direct radiolabeling of nanoparticles [14].

mannose, galactose and glucose across the BBB [16].

positron-emission-tomography (PET). In single-photon emission computed tomography (SPECT), a gamma-emitting tracer allows for three dimensional visualization of the drug [9]. The radioisotope is either administered with the drug or directly bound to the biologically active molecule such as siRNA, so that their volume of distribution can be determined easily. Accurate anatomic estimates can be obtained by combining SPECT with CT or MRI. This approach is less expensive in comparison to other nuclear medicine imaging modalities [10]. Conventional SPECT suffer from poor limitation. However, recent advances involving pinhole-SPECT has

Another promising modality for imaging drug delivery to tumor is positronemission-tomography (PET). PET tracers are administered with the drug or are bound to the carrier like nanoparticles [12]. The PET scan can be correlated with CT

Similar to gadolinium and SPECT contrast agents, PET tracers can be infused concurrently with drug or bound to the delivery system, such as nanoparticles [12]. When PET is coupled with CT, molecular movement can be correlated with anatomy, with measurement of area of diffusion of tracer or tracer-incorporated carrier. PET imaging can estimate the borders of a tumor through the use of tracers that are derivatives of amino acid such as O-(2-[18F]fluoroethyl)-L-tyrosine (FET) thus allowing precise assessment of drug distribution relative to tumor volume than MRI [13]. Limitations of PET and SPECT imaging include radiation exposure, the high cost, and short-lived nature of PET tracers. Another important limitation similar to gadolinium agents in MRI is the tracer has to directly couple to the delivery agent; otherwise the measurement of the area of diffusion is indirect. These limitations

**3. Nanocarrier-mediated CNS delivery of diagnostic and therapeutic** 

Drug delivery across the BBB requires knowledge of both "barrier" and permeability properties of the brain endothelial cells. Transport across BBB may involve simple diffusion, facilitated diffusion, diffusion through aqueous pores, and active transport through protein carriers. In case of simple diffusion solute molecules travels along concentration gradient. Facilitated diffusion involves binding with specific membrane-traversing protein, coupled with movement along the concentration gradient. Charged ions and solutes cross the BBB by diffusion through aqueous pores. Active transport of solutes through protein carrier against concentration gradient involves expenditure of ATP. The presence of large number of mitochondria in the endothelial cells is thought to provide the required energy in form of ATP [15]. This mechanism involves an alteration in the affinity of a carrier for the solute molecules as it travels across the BBB. While designing nanocarrier mediated CNS delivery, transporter systems involved in ferrying essential molecules such as glucose are of utmost importance. These systems can be employed for delivery of potential nanotheranostics across the BBB. There are five types of sodium-independent glucose transporters (GLUT) which transport 2-deoxyglucose, 3-O-methylglucose, mannose, galactose and glucose across the BBB. The most important being 45–55 kDa glycosylated protein GLUT-1. It is mostly present in endothelial cells of arterioles, venules and capillaries, wherein it facilitates movement of D-glucose from the peripheral circulation into the brain. Other worth mentioning glucose transporters are GLUT-3 in brain neurons and GLUT-5 in microglial cells in the brain. They transport 2-deoxyglucose, 3-O-methylglucose,

#### *Radiolabelled Nanoparticles for Brain Targeting DOI: http://dx.doi.org/10.5772/intechopen.92668*

*Medical Isotopes*

tumor and minimal residual disease [2, 3].

of isolated tumor cells [1, 5].

**2. Understanding WHO Classification of CNS tumors**

novel targeted therapies for specific glioma subtypes [2, 8].

Drug delivery to tumor can be monitored using nuclear medicine imaging techniques like single-photon emission computed tomography (SPECT),

Gliomas are the most frequent, very diverse group of intrinsic tumors of the central nervous system and are conventionally classified in harmony to their microscopic alikeness with recognized cells of origin according to glial precursor cell families. Major groups consist of diffuse gliomas, categorized by widespread growth into the adjoining CNS parenchyma, and more confined "nondiffuse" gliomas, with pilocytic astrocytoma and ependymomas [6]. The fourth edition of the WHO Classification of CNS tumors published in 2016 has essentially changed the classification of diffuse gliomas. These tumors are presently defined based on presence/absence of IDH mutation and 1p/19q codeletion. It can be attributed to massive expansion of knowledge on molecular alterations in tumors of the central nervous system (CNS) [2]. Until now, tumors were defined based on their histology. Any molecular information was mainly provided as supplementary information within histologically defined categories. Current advances in the molecular conceptualization of gliomas recommend some probable reasons for the failure of targeted therapies in gliomas. Specially, the histologic-based glioma categorization comprises of multiple molecular subtypes with discrete biology, usual history, and diagnosis. These observations have resulted in improvement in diagnosis and classification by the World Health Organization [7]. These perceptions regarding glioma biomarkers and subtypes highlight several clinical challenges. Firstly, the field is witnessing the struggle of reconsidering the results of previous studies and retrospective data using the new classifications to explain prognostic assessments and treatment recommendations for patients. Secondly, the new classification requires changes in the design and stratification of future clinical trials. Hence, these observations offer the required framework for the growth and evaluation of

short range emission could be used for treatment retreating tumors of small size. Alpha particles deliver a high fraction of their energy inside the targeted cells, leading to highly efficient killing. This makes them suitable for targeting cells of isolated

Radioimmunotherapy, radiopeptide therapy and radionanoparticles are three important strategies of nuclear medicine for glioblastoma therapy. The four main prerequisites for successful radionuclide therapy for glioblastoma are selection of an appropriate target (integrin, tenascin, cadherin, EGFR, chemokine receptors or neurokinin receptors), physicochemical properties of the radionuclide, physicochemical properties of the targeting vector and its size [4]. For therapeutic purposes, nuclear medicine practitioners typically use β− particle emitters like 131I, 90Y, 186/188Re, and 177Lu. These radioisotopes have been coupled with nanoparticles, monoclonal antibodies, or peptides for treatment of glioblastoma. These radiopharmaceuticals have resulted in maintenance and/or improvement of the neurological status with only short-term side effects. The evidence for glioblastoma targeted radiotherapy has not only proven for β− particle emitters but also for α particle emitters. 213Bi, 211At, and 225Ac are some of the particle emitters which are recently attracting the interest of the scientific community. They are capable of delivering high amount of their energy within few micrometers close to their emission point in comparison to some few millimeters for β− particles. The α particles have been found highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting

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positron-emission-tomography (PET). In single-photon emission computed tomography (SPECT), a gamma-emitting tracer allows for three dimensional visualization of the drug [9]. The radioisotope is either administered with the drug or directly bound to the biologically active molecule such as siRNA, so that their volume of distribution can be determined easily. Accurate anatomic estimates can be obtained by combining SPECT with CT or MRI. This approach is less expensive in comparison to other nuclear medicine imaging modalities [10]. Conventional SPECT suffer from poor limitation. However, recent advances involving pinhole-SPECT has improved the resolution to millimeter level [11].

Another promising modality for imaging drug delivery to tumor is positronemission-tomography (PET). PET tracers are administered with the drug or are bound to the carrier like nanoparticles [12]. The PET scan can be correlated with CT scan in order to determine path of diffusion of tracer.

Similar to gadolinium and SPECT contrast agents, PET tracers can be infused concurrently with drug or bound to the delivery system, such as nanoparticles [12]. When PET is coupled with CT, molecular movement can be correlated with anatomy, with measurement of area of diffusion of tracer or tracer-incorporated carrier. PET imaging can estimate the borders of a tumor through the use of tracers that are derivatives of amino acid such as O-(2-[18F]fluoroethyl)-L-tyrosine (FET) thus allowing precise assessment of drug distribution relative to tumor volume than MRI [13]. Limitations of PET and SPECT imaging include radiation exposure, the high cost, and short-lived nature of PET tracers. Another important limitation similar to gadolinium agents in MRI is the tracer has to directly couple to the delivery agent; otherwise the measurement of the area of diffusion is indirect. These limitations can be overcome by direct radiolabeling of nanoparticles [14].
