Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 8

Atta-ur-Rahman, Zareen Amtul

• Publisher: Bentham Science Publishers
• Year: 2020
• ISBN:
  9789811470080
• Topic: Medicine
• Subtopic: Neurology

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology. The eighth volume of this series features reviews that cover the following topics related to the treatment of a variety of CNS disorders, related diseases and basic research: - Emerging Innovative Therapies of Spinal Muscular Atrophy: Current Knowledge and Perspectives - Obesity Induced by The Neurological Drugs - Molecular Mechanism of Nervous System Disorders and Implications for New Therapeutic Targets - Glioma Imaging and Novel Agents - Screening Models for Neuroleptic Drug-Induced Hyperprolactinemia: A Mini-Review

Glioma Imaging and Novel Agents

Mine Silindir-Gunay^*

Hacettepe University, Faculty of Pharmacy, Department of Radiopharmacy, 06100, Sıhhiye, Ankara, Turkey

Abstract

Glioma is one of the most frequently observed and aggressive brain tumors. Glioma forms 50-60% of brain tumors including astrocytoma, oligodendroglioma, and glioblastoma. Although the integrity of the blood-brain barrier (BBB) is destroyed somehow in glioblastoma (high-grade glioma) patients, similar to many central nervous system diseases, the main anatomical obstacle remains BBB in effective diagnosis, imaging, and therapy.

The survival rate of glioblastoma patients is very low. Early and accurate diagnosis of glioma is essential for therapy chance. When compared with other techniques, non-invasive medical imaging methods provide high specificity and sensitivity. Although MRI is one of the most commonly used modalities in glioma diagnosis and imaging, it possesses limited differentiation in tumor recurrence and pseudoprogression after radiotherapy and combined chemotherapy. Improved MRI techniques can exhibit higher potential in evaluating the pathological features and grading of gliomas before treatment. As a novel method, molecular imaging techniques such as PET/CT can detect genetic mechanisms and related molecular and metabolic differentiation for accurate diagnosis of diseases.

¹⁸F-FDG, one of the most commonly used PET radiopharmaceuticals, is highly accumulated in the cerebral cortex. Therefore, ¹⁸F-FDG is a non-specific agent in glioma diagnosis and imaging. Non-specific radiopharmaceuticals are not sufficient depending on low sensitivity and specificity in early diagnosis and imaging of proliferation index of tumor cells, the place of hypoxic focuses, tumor load, differentiation of tumor/necrosis, and tumor/inflammation and therapy monitoring of glioma. Therefore, target-specific radiocontrast/contrast agents have been searched for accurate diagnosis, imaging, and therapy monitoring of glioma. Specific PET agents provide differentiation of tumor, necrosis, or inflammation. More specific glioma imaging agents including novel specific Gd or SPIO comprising MRI contrast agents, amino acid tracers like ¹⁸F-FET, and peptide tracers like αvβ3 integrin specific ⁶⁸Ga-RGD and radiolabeled, targeted drug delivery systems have been searched for accurate and early diagnosis of all stages of glioma.

Keywords: Blood-brain barrier, Diagnosis, Enhanced-permeability and retention effect, Glioma, Glioma targeting, Imaging, Multifunctional drug delivery systems, Nanocarriers, Radiopharmaceuticals, Specific probes, Theranostics for glioma.

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^* Corresponding author Mine Silindir-Gunay: Hacettepe University, Faculty of Pharmacy, Department of Radiopharmacy, 06100, Sıhhiye, Ankara, Turkey; Tel: [phone], Fax: [phone]; E-mail: [email protected]

INTRODUCTION

Glioblastoma is one of the most commonly observed and aggressive brain tumors. It takes its roots from star-shaped glial tissues. Glial cells support nerves, protect the BBB and, ensure continuity. Glioma is an umbrella term comprising astrocytoma, oligodendroglioma, and glioblastoma. Glioma is originated from glial tissues which are called astrocytes that gained abnormal features and shapes [1^-7].

Glioblastoma is the primary malignant brain tumor and has the worst therapy potential. World Health Organization (WHO) defines glioblastoma as the highest grade (IV grade) brain tumor [8]. Grading of diffuse glioma according to WHO 2007 was defined as Astrocytoma (Grade II), Oligodendroglioma (Grade II), Oligoastrocytoma (Grade II), Anaplastic-astrocytoma/oligodendroglioma (Grade III) and Glioblastoma (Grade IV) [8]. However, according to WHO 2016, molecular parameters in addition to histology have been initiated to use for the classification of CNS tumors. In this version, a major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors was defined incorporating new entities based on both histology and molecular features such as glioblastoma, IDH-wildtype, and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M–mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumor with multilayered rosettes, C19MC-altered [9]. The incidence rate of glioma is 3.19 per 100,000 persons in the USA and a median age of 64 years. It is 1.6 times higher in males compared to females and it is uncommon in children [10].

This tumor may also attack both hemispheres of the brain [1^-3]. It may also develop high vascularization into the surrounding brain parenchyma and extensive infiltration [4^-7]. Therefore, survival is fairly poor for glioma patients. Only a few of them survive for 2.5 years following diagnosis [10]. However, early diagnosis and imaging of the disease are essential to enhance therapy efficacy and chances of survival. When compared with other techniques, non-invasive molecular imaging and advanced Magnetic Resonance Imaging (MRI) techniques possess high importance for the diagnosis of neurological diseases and alterations formed before and after tumor depending on high specificity and sensitivity. Molecular imaging provides information about monitoring of quantification of gene and protein functions, protein-protein interactions and signal transduction pathways, non-invasive detection, imaging and characterization related to the molecular pathophysiology of a specific disease [11, 12]. In this way, a more accurate and specific diagnosis of glioma can be obtained by the multidisciplinary cooperation of different branches including Nuclear Medicine, Radiology, Neurology, Neurosurgery, Oncology, and Pharmacy. To perform effective and specific molecular imaging, it is essential to establish molecular imaging probes conjugated with mAbs, antibody fragments, ligands, enzymes, substrates, peptides, proteins and markers that are specific to a receptor, amino acid or enzyme expressed in the target organ/tissue within the body. These probes can be used for imaging of the last product in the gene expression of a specific protein for binding to a target protein or markers after the radiolabeling process. These interactions are performed due to receptor-radionuclide binding or enzyme-radionuclide substrate reaction [12^-14]. Recently, the design of novel radiocontrast/contrast agents for sensitive and accurate imaging is getting popular and attractive. Molecular imaging can detect in vivo mechanisms and cellular and molecular pathways of the diseases in a dynamic a...