**4. Paradigm shift in glioma diagnosis and treatment strategies**

The WHO 2016 Classification of gliomas represents a paradigm shift as; for the first time, the definition of many of these neoplasms is partly based on genetic characteristics based on molecular markers. This was a major step forward toward a more precise diagnosis of gliomas and will in the course of time certainly facilitate improved therapeutic management of the patients suffering from these tumors. Diffuse gliomas are the most common intrinsic CNS neoplasms, found in adults. On the basis of histopathological analysis, these gliomas were conventionally diagnosed as diffuse astrocytomas (with glioblastoma as it is most common and malignant representative), oligodendrogliomas, or as tumors with a mixed astrocytic and oligodendroglial phenotype (oligoastrocytomas) [6]. Within these subgroups, a malignancy grade (WHO grade II, III or IV) was assigned based on the presence/ absence of marked mitotic activity, necrosis and florid microvascular proliferation. The major change can be attributed to use of isocitrate dehydrogenase (IDH mutation) as a marker in diffuse glioma classification. The categorization of diffuse gliomas on the basis of genotype involves high incidence of point mutations in isocitrate dehydrogenase 1 and 2 (*IDH1*/*IDH2*) in WHO grade II and III astrocytomas, oligodendrogliomas, oligoastrocytomas and secondary glioblastomas. Lower grade neoplasms usually develop into secondary glioblastomas [8]. Hence, it became clear that tumors with identical histology can lead to different clinical outcome such as IDH-wildtype and IDH-mutant diffuse gliomas. Many histologically similar WHO grade II and WHO grade III IDH-wild type diffuse gliomas exhibit molecular characteristics like glioblastoma. These facts ultimately led to inclusion of IDH mutation as a crucial marker for glioma classification and the introduction of, genetically defined entities: diffuse astrocytoma, IDH-mutant; anaplastic astrocytoma, IDHmutant; oligodendroglioma, IDH-mutant; anaplastic oligodendroglioma, IDHmutant; and glioblastoma, IDH-mutant [7]. The molecular features of IDH-mutant glioma outweigh the histological diagnosis. A tumor having histology of an astrocytoma, detection of complete 1p/19q codeletion leads to diagnosis of oligodendroglioma. Likewise, for diffuse, IDH-mutant gliomas with oligodendroglial phenotype with complete absence of 1p/19q codeletion, the collective diagnosis may be astrocytoma, IDH-mutant and 1p/19q-non-codeleted [8]. Based on IDH mutation status, glioblastomas were reclassified as glioblastoma, IDH-wildtype and glioblastoma,

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side-effects [28].

(

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

characteristics [22, 23].

**5. Multimodal tumor imaging and therapy**

IDH-mutant. This latter category largely overlaps with what previously described secondary glioblastoma based on clinical, radiological and/or pathological evidence of a lower grade precursor lesion. Patients with a secondary glioblastoma or IDHmutant glioblastoma are normally younger and have improved diagnosis than those with glioblastoma, IDH-wildtype. Analogous to grade II and grade III oligoastrocytic tumors, most glioblastomas with oligodendroglioma as explained in the WHO 2016 Classification are part of one of the genetic subgroups of diffuse glioma [7, 8]. One of the treatment strategies which are catching the attention of oncologist is nanotechnology. Nanoparticles (NP) are entities possessing diameter of 10–200 nm that hold great possibilities for design and biological applications. There has been an upsurge in development of nanodevices for diagnosis and treatment of brain tumors. Nanoparticles are carriers that can be designed to ferry one or more types of molecules to brain including MRI contrast agents, fluorescent and visible dyes, chemotherapeutic agents and photosensitizers. The targeted delivery of nanoparticles to brain tumors can be augmented by altering their particle size and surface

There has been moderate impact of targeted therapies in glioma. The therapies that have demonstrated a significant survival benefit for gliomas in Phase III clinical trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. An emerging field in glioblastoma nuclear medicine is use of radionanoparticles. These radioactive nanocarriers can be used passively as a simple tumor brachytherapy or can be actively used with a specific targeting to vectorize a large amount of radioactivity. The targeting is usually directed against a glioblastoma-specific antigen or receptor. Antigen targets, like epidermal growth factor receptor (EGFR), tenascin, or DNA histone H1 complex. Radiolabeled antibodies and peptides hold promise for molecular radiotherapy but are often limited by a low payload resulting in inadequate delivery of radioactivity to tumor tissue and, therefore, inadequate therapeutic effect and adverse effects due irradiation of normal tissues [24]. Song et al. developed a synthetic method of radiolabeling indium-111 (111In) to epidermal growth factor (EGF)-gold nanoparticles

111In-EGF-Au NP) with a high payload [25]. By using radiolabeled nanoparticles, comparatively higher payloads are obtained due to large surface area to volume ratio. This results in multivalent effect of nanoparticles, thus accommodating a large number of targeting ligands, such as antibodies, peptides or aptamers on a single nanoparticle. This facilitates maximal binding to the molecular target in vivo, thus enhancing delivery of radioactivity to target tissue with improved imaging and therapeutic efficacy. PEGylation of nanoparticles and alteration of their surface properties improves their stability and mean residence time in vivo [26]. It also permits loading a combination of imaging, radiotherapeutic and/or chemotherapeutic moieties for multimodal tumor imaging and therapy [27]. Antibodies, radiolabeled antibodies, antibody fragments or peptides because of their small size easily penetrate surrounding normal tissues. Loading onto nanoparticles limits their penetration through normal vasculature and capillaries, thus minimizing their

Different nanocarriers such as metallofullerenes, liposomes, or lipid nanocapsules have been used to deliver radionanoparticle passively. A typical metallofuller-

ene (177Lu-DOTA-f-Gd3N@C80) radionanoparticles when administered by convection-enhanced delivery (CED) in brain tumor model showed an improved *Radiolabelled Nanoparticles for Brain Targeting DOI: http://dx.doi.org/10.5772/intechopen.92668*

*Medical Isotopes*

Another significant transport system that works in an analogous manner is P-glycoprotein multiple drug resistant protein (P-gp, MDR1). It has been comprehensively investigated as a possible carrier for drug delivery. This efflux transporter is usually expressed on luminal surface of endothelial cells, astrocytes and microglial cells. It prevents toxins from gaining entry into the brain parenchyma [17, 18]. Anticancer agents like Vinca alkaloids, anthracyclines, and taxanes are substrates for MDR1 are transported by Pgp. It limits their accumulation in the brain. Recently, it has been found that MDR1 regulation is altered by various disease conditions, and, in turn, diseases of the brain influence MDR1 expression [19, 20]. The presence of large number of receptors at the surface of BBB can be utilized by potential nanocarriers for enhanced brain by coupling with receptor-specific molecules or analogues. A large number of molecules such as insulin, insulin-like growth factors (IGF-1 and IGF-2), leptins, and transferrin can be transported into the brain following receptor-mediated endocytosis [13]. The nanoparticles should be designed to bypass efflux transport systems present at the luminal side (such as MDR1). Instead, nanoparticles could be substrates of transport mechanisms enhancing the passage of specific molecules like GLUT-1, IGF-1, and IGF-2 across the BBB [21].

**4. Paradigm shift in glioma diagnosis and treatment strategies**

The WHO 2016 Classification of gliomas represents a paradigm shift as; for the first time, the definition of many of these neoplasms is partly based on genetic characteristics based on molecular markers. This was a major step forward toward a more precise diagnosis of gliomas and will in the course of time certainly facilitate improved therapeutic management of the patients suffering from these tumors. Diffuse gliomas are the most common intrinsic CNS neoplasms, found in adults. On the basis of histopathological analysis, these gliomas were conventionally diagnosed as diffuse astrocytomas (with glioblastoma as it is most common and malignant representative), oligodendrogliomas, or as tumors with a mixed astrocytic and oligodendroglial phenotype (oligoastrocytomas) [6]. Within these subgroups, a malignancy grade (WHO grade II, III or IV) was assigned based on the presence/ absence of marked mitotic activity, necrosis and florid microvascular proliferation. The major change can be attributed to use of isocitrate dehydrogenase (IDH mutation) as a marker in diffuse glioma classification. The categorization of diffuse gliomas on the basis of genotype involves high incidence of point mutations in isocitrate dehydrogenase 1 and 2 (*IDH1*/*IDH2*) in WHO grade II and III astrocytomas, oligodendrogliomas, oligoastrocytomas and secondary glioblastomas. Lower grade neoplasms usually develop into secondary glioblastomas [8]. Hence, it became clear that tumors with identical histology can lead to different clinical outcome such as IDH-wildtype and IDH-mutant diffuse gliomas. Many histologically similar WHO grade II and WHO grade III IDH-wild type diffuse gliomas exhibit molecular characteristics like glioblastoma. These facts ultimately led to inclusion of IDH mutation as a crucial marker for glioma classification and the introduction of, genetically defined entities: diffuse astrocytoma, IDH-mutant; anaplastic astrocytoma, IDHmutant; oligodendroglioma, IDH-mutant; anaplastic oligodendroglioma, IDHmutant; and glioblastoma, IDH-mutant [7]. The molecular features of IDH-mutant glioma outweigh the histological diagnosis. A tumor having histology of an astrocytoma, detection of complete 1p/19q codeletion leads to diagnosis of oligodendroglioma. Likewise, for diffuse, IDH-mutant gliomas with oligodendroglial phenotype with complete absence of 1p/19q codeletion, the collective diagnosis may be astrocytoma, IDH-mutant and 1p/19q-non-codeleted [8]. Based on IDH mutation status, glioblastomas were reclassified as glioblastoma, IDH-wildtype and glioblastoma,

**120**

IDH-mutant. This latter category largely overlaps with what previously described secondary glioblastoma based on clinical, radiological and/or pathological evidence of a lower grade precursor lesion. Patients with a secondary glioblastoma or IDHmutant glioblastoma are normally younger and have improved diagnosis than those with glioblastoma, IDH-wildtype. Analogous to grade II and grade III oligoastrocytic tumors, most glioblastomas with oligodendroglioma as explained in the WHO 2016 Classification are part of one of the genetic subgroups of diffuse glioma [7, 8]. One of the treatment strategies which are catching the attention of oncologist is nanotechnology. Nanoparticles (NP) are entities possessing diameter of 10–200 nm that hold great possibilities for design and biological applications. There has been an upsurge in development of nanodevices for diagnosis and treatment of brain tumors. Nanoparticles are carriers that can be designed to ferry one or more types of molecules to brain including MRI contrast agents, fluorescent and visible dyes, chemotherapeutic agents and photosensitizers. The targeted delivery of nanoparticles to brain tumors can be augmented by altering their particle size and surface characteristics [22, 23].
