The Blood–Brain Barrier Challenge for the Treatment of Brain Cancer, Secondary Brain Metastases, and Neurological Diseases
2015
Formation of metastases from various tumor entities in the brain is a major problem for the treatment of advanced cancer. We describe target molecules and tools for the delivery of small molecules or proteins across the blood-brain barrier (BBB), and the treatment of brain tumors and metastases with antibody-related moieties. In addition, drugs preventing formation of metastases or interfering with the growth of established metastases are described, as well as pre-clinical metastasis models and corresponding clinical data. Furthermore, we discuss the delivery of effector proteins and antibody-based moieties fused with an antibody-based scaffold across the BBB in several model systems which might be applicable for the treatment of brain metastases. Although some primary brain tumors such as glioblastoma are associated with a dismal prognosis (1), metastatic lesions originating from various primary tumors outside the brain are in fact responsible for 90% of cancer deaths from brain malignancies (2). Thus, primary brain tumors such as glioblastoma mainly act through local invasive growth and rarely metastasize to organs outside of the brain, whereas many peripheral tumors, such as pancreatic carcinoma or small cell lung carcinoma (SCLC), have usually metastasized to distant organs before diagnosis (1, 3). Moreover, while metastases derived from certain types of tumors such as SCLC colonize various distant organs, others exhibit a pronounced organ-specific tropism of metastasis (3-7). Prostate cancer preferentially metastasizes to the bones, colon cancer to the liver, and sarcoma to the lungs (4). Importantly, distant brain metastases most commonly arise from primary tumors of the lung (50-60%), breast (15-20%), melanoma (5-10%) and the gastrointestinal tract (4-6%) (8, 9). The incidence of such brain metastasis is estimated to be approximately 170,000/year in the USA, 10-times the number of primary brain tumors (10). Accordingly, successful treatment of primary brain tumors and brain metastases poses a major medical problem which almost certainly will be significantly affected once efficient and reliable delivery of drugs into the brain become available. The Blood-Brain Barrier (BBB) The BBB is a highly selective barrier regulating the uncontrolled diffusion of most molecules into the brain. Thus, tissue homeostasis is maintained by enabling the transport of selected substances necessary for the brain, while access to the brain is blocked for most other molecules, most notably for toxic metabolites and xenobiotics (11). Thus, for a small molecule, free diffusion across the BBB requires both lipophilicity and a molecular mass smaller than 400-500 Da (12, 13). Most large molecules such as immunoglobulins, however, are not allowed to cross the BBB unless transported actively into the brain. On the other hand, due to the presence of neonatal fragment crystallizable region (Fc) receptors (FcRn) and other clearance mechanisms, IgG antibodies are actively transported from the brain into the circulation (14). In patients with brain tumors, leakiness of the BBB has been observed (15). The complete surface area of the BBB comprises approximately 20 m 2 , with a total length of capillaries in the brain of approximately 600,000 m (11). The pivotal component of the BBB (Figure 1) is a monolayer of endothelial cells in brain capillaries which are connected by tight junctions (TJ). Absence of fenestration also contributes to the barrier properties of brain endothelial cells. In addition, pericytes, astrocytes and neurons are involved in
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