**1. Introduction**

Gliomas are the deadliest primary central nervous system (CNS) neoplasms arising from rapid proliferation of glial cells, the non-neuronal cells present in brain. Based on histopathologic features and progression of the disease, gliomas are classified by WHO into four grades: grade I (pilocytic astrocytoma), grade II (astrocytomas and oligodendrogliomas), grade III (anaplastic astrocytomas and oligodendrogliomas), and grade IV (glioblastoma multiforme). The low-grade (I and II) glial tumors often evolved with time into high-grade (grade IV) glioblastoma multiforme (GBM). However, irrespective of their grading, glial tumors almost invariably exhibit marked infiltrative growth pattern with tumor cells traveling long distances away from their origin into the surrounding healthy brain tissue. Furthermore, they are highly proliferative along with their significant angiogenic potential and resistance to apoptosis. GBM has a median survival of 14–17 months post diagnosis and only 3–5% survivability beyond 5 years. Current standard of care to treat gliomas includes safe surgical resection of the tumor followed by radiotherapy and chemotherapy. Despite significant advances in the cancer treatment, therapeutic success against gliomas remained an unmet challenge mainly because of their diffusive infiltrating growth pattern with rapid proliferation rate

and physiological location, which made them difficult to cure completely either by surgical excision or application of radiotherapy/chemotherapy [1, 2]. More often than not rapid recurrence of tumor ensues. Poor drug accumulation in glioblastoma tissue, unfavorable pharmacokinetic behavior, and toxicity to off-target organs are retarding the clinical success of systemic chemotherapy of glioblastoma.

#### **1.1 Physiology and anatomy of human brain**

Toward developing an effective therapeutic strategy for combating glioblastoma, a basic understanding of brain physiology is very important. Brain is an integral part of the central nervous system. Primary brain cells include equal number of neuron and glial cells [3]. Where neurons connect different body parts by transmitting information, glial cells provide structural support and protection to the neurons. Both cells together organize into specialized structures, which can be classified as gray matter (dominated by cell bodies) and white matter (dominated by axons). The three major subdivisions of human brain are the cerebrum, cerebellum, and the brain stem (**Figure 1**) [4]. The largest part cerebrum is divided into the right and left hemispheres along the mid-sagittal plane. These hemispheres are made up of an outer layer of gray matter named as the cerebral cortex responsible for language and information processing. Cerebral cortex cells communicate with each other and with the spinal cord via the underlying cerebral white matter. Communication between the two cerebral hemispheres primarily occurs via a major white matter tract called the corpus callosum. The cerebellum contains a similar kind of gray and white matter organization but at a smaller scale. It functions primarily to control balance and coordinated movement. The brain stem, responsible for involuntary functions such as heart rate and breathing, connects the brain to the spinal cord. It also contains both gray and white matter regions. However, unlike in cerebrum and cerebellum, they are not organized into inner and outer layers. Most of the brain tumors occur in the parenchymal space of the cerebrum [5]. However, getting drugs into the brain is much more difficult than that into other body tissues as brain tissue is highly protected both externally and internally. Skull externally protects brain tissue and regulates intracranial tissue pressure by constraining the volume [6], which limits the regional mode of drug delivery to brain. Brain is internally protected by the blood-brain barrier (BBB), which prevents random entry of

#### **Figure 1.**

*Basic anatomy of human brain; cerebrum, cerebellum, and brain stem are the three major subdivisions of human brain.*

molecules from blood circulation into brain tissue making delivery of systemically administered drugs to brain an arduous task.
