The application of magnetic nanoparticles for the treatment of brain tumors.

Abstract

Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common and difficult primary brain tumor to treat (Braun et al., 2012). Even when detected early, the median survival rate for patients is 12–15 months (Adamson et al., 2009; Johnson and O'Neill, 2012). The challenge in treating GBM arises from its resistance to therapies such as radiotherapy and chemotherapy. GBM tumors are quite infiltrative into the surrounding normal brain permitting tumors to recur locally in the majority of patients. The current standard of care treatment for GBM involves surgery and radiation, with concurrent and adjuvant chemotherapy (Stupp et al., 2005). Surgery permits the bulk of a GBM tumor to be removed in most cases. All patients have residual tumor cells residing away from the resection cavity that eventually lead to local tumor recurrence and the demise of the majority of patients (Hou et al., 2006). The infiltrating GBM cells reside centimeters away from the main tumor mass in normal brain making it difficult for complete surgical removal (Kim et al., 2014). Chemotherapy and radiotherapy of patients after surgery attempts to target these cells to prolong overall patient survival. The blood brain barrier (BBB) represents another challenge to the treatment of GBM tumors by preventing the accumulation of most chemotherapeutics into the brain to target the infiltrative cancer cells (Salazar et al., 1976; Bidros and Vogelbaum, 2009). Surgery and adjuvant therapies pose risks to the patient such as neurologic deficits and systemic toxicities. Known side effects of radiation therapy with chemotherapy for brain tumors include chronic fatigue, nausea, and cognitive deficits (Loehrer et al., 2011). The BBB remains a formidable challenge in the treatment of GBM and malignant brain tumors. Its selective permeability is due to the presence of specialized endothelial cells, astrocytes, pericytes, and neuronal terminals (Tajes et al., 2014). The semi-permeable membrane that comprises the BBB prevents sufficient exposure of tumors to most chemotherapeutic drugs that are commonly used to fight tumor progression (Liu et al., 2010). Local disruption of the BBB is found within GBM tumors. The tumor vessels in GBM tumors are abnormal both structurally and functionally (Batchelor et al., 2007). The abnormal tumor vessels further impair delivery of therapeutics and create a hypoxic microenvironment that can reduce the effectiveness of radiation and chemotherapy. Antiangiogenic therapy attempts to normalize the tumor vasculature and improve the tumor microenvironment (Jain, 2001, 2005). Outside of the main tumor mass, the BBB is intact where brain cancer cells infiltrate into the surrounding normal brain. The oral chemotherapy agent, temozolomide (Temodar), can penetrate the BBB and has resulted in prolongation of overall survival patient survival by several months (Stupp et al., 2005). The challenges associated with the treatment of GBM tumors require novel approaches for a greater impact on patient survival and quality of life for patients.