Date: 30th September 2024 | Issue #2
Brain tumors occur when abnormal cells grow in the brain or nearby tissues, such as the pituitary gland, nerves, pineal gland, or membranes that cover the brain. Brain tumors that begin in the brain are called primary brain tumors, while those that spread to the brain from other sites are called metastatic brain tumors. Glioblastoma (GB) is the most common and malignant type of primary brain tumor, accounting for 55% of all primary brain tumors (Rodriguez et al., 2022; Louis et al., 2019). Despite advances in understanding the biology of brain tumors, much has remained the same in their treatment in the past decade. Conversely, the overall prognosis remains dismal for patients with GB due to a local recurrence despite the standard treatments such as chemotherapy, radiotherapy, and surgery (Stupp et al., 2009). To date, the Food and Drug Administration (FDA) has approved only four systemic therapies for GB, including temozolomide (TMZ), lomustine, carmustine, and bevacizumab. Temozolomide lomustine, and carmustine are simple alkylating agents (they add an alkyl chemical group to DNA, interfering with replication), while bevacizumab is an antibody therapy that blocks a growth factor (vascular endothelial growth factor – VEGF) that promotes the development of tumor-associated blood vessels. Even with the current treatment options, the median survival of patients with GB is approximately 14.6 months, and their 5-year survival rate is less than 5% (Stupp et al., 2009; Gilbert et al., 2013).
The origin of GB is still unclear. Initially, it was thought that central nervous system (CNS) cells develop mutations that give rise to GB (Geraldo et al., 2019; Visvader, 2011). Others have suggested that GB arises from neuronal cells (Liu et al., 2011; Alcantara et al., 2016), but the cellular heterogeneity of GB makes it extremely hard to accurately identify its cell of origin. More recently, glioblastoma stem cells (GSCs), which represent a subpopulation of self-renewing cells involved in tumor initiation and maintenance, have emerged as the culprits as they have shown to have the ability to self-renew and differentiate into a heterogeneous population of cancer, to be responsible for cancer relapse and drug resistance (Rodriguez et al., 2022; Ciurea et al., 2014; Singh et al., 2004).
All organisms with a well-developed CNS have a blood-brain barrier (BBB) (Abbott, 2005; Zhou et al., 2018). The BBB is a membrane barrier that separates blood from the extracellular fluid of the brain in the CNS of most vertebrates, thereby protecting the brain from foreign substances in the blood that may damage the brain, thus keeping a constant brain environment (Zhou et al., 2018; Mayer et al., 2009). Due to the presence of the junctions between cells in the BBB, the passage of the many molecules, including drugs, is primarily restricted (Sandoval and Witt, 2008). The BBB markedly limits brain distribution of many cancer pharmaceuticals, including monoclonal antibodies and hydrophilic molecules that do not readily cross the cell membrane. For molecules that readily go across the cell membrane into the cells, endothelial cells express pumps that get rid of these molecules (Sarkaria et al., 2018). Only small molecules such as water, some gasses, and some lipid-soluble compounds can easily penetrate through the BBB by passive diffusion.
On the other hand, transporting large molecules with high electric charge, polarity, and hydrophilicity (i.e., glucose, amino acids, and most drugs) has to rely on specific proteins via active transport routes (Zheng et al., 2003). Thus, the delivery and release of drugs into the brain is a challenging topic, and various strategies have been developed to efficiently improve the release of drugs into the brain. These strategies include chemical modification of the drugs to allow them to cross the BBB. Second, temporary disruption of the tight junctions that hold the BBB in place can also permit entry of drugs into the brain. Finally, neurosurgery- and nanoparticle-assisted drug delivery into the brain are additional options (Koo et al., 2006). Of these methods, nanoparticle-assisted drug delivery across the BBB is a relatively optimistic approach. It offers advantages such as non-invasiveness, low cost, long-term stability in circulation, ease of synthesis, high targeting efficiency, and high controllability to load and release drugs across the BBB (Zhou et al., 2018; Nance et al., 2014).
The contribution of the BBB to treatment failure in GB raises the need for improved efforts to develop BBB-penetrating agents, optimize BBB-disruption technologies, and refine implantable drug delivery technologies that bypass the BBB and deliver therapeutic concentrations throughout an infiltrating tumor volume.
Dr Lucy Macharia is a researcher at ICRF-Kenya and a postdoctoral research fellow in the Prince Cancer Group and a part-time tutor/demonstrator at the Department of Human Biology at the University of Cape Town.